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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to multi-directional, reciprocating electrical currents. The invention also relates to an apparatus and method for generating the multi-directional currents, and to applications of the generating apparatus and method.
The multi-directional currents of the invention are generated in a current carrying medium by cyclically reversing the direction of a conventional current applied to at least one of a plurality of electrodes, so that an electromotive force (EMF) pulse travels from one side of the at least one electrode to the other, changing the direction of current flowing through the medium between two or more electrodes.
The multi-directional electric currents have the effect of accelerating processes that rely on interaction between a current and the medium that carries the current, and of eliminating asymmetries that can lead to scaling or premature wear in batteries and other electrolytic systems. The medium that carries the multi-dimensional currents may be an electrolyte, gas, gel, semiconductor, or any other medium capable of carrying current between two electrodes, and having at least two dimensions so as to enable variation in the current direction.
By way of example and not limitation, the multi-directional electrical currents of the invention may be used to (i) increase the efficiency of hydrogen generation by electrolysis of water (while at the same time preventing scaling and purifying the water), (ii) extend the life of batteries such as nickel-metal hydride cells, and of capacitors, by symmetrically charging and discharging the batteries or capacitors, (iii) provide a power source for electromagnetic projectile weapons and similar devices, and (iv) increase the efficiency of plasma generation or light conversion in cold cathode systems.
Other potential applications of the multi-directional electric currents of the invention, and of the apparatus and method for generating the currents, include computers, communications, drug and chemical development, medical treatment of cancers, anti-gravity experiments, transportation, energy, water treatment, genetic research in humans, plants, and animals, and aeronautical propulsion systems, as well as fuel cell and PEM electrolysis systems utilizing proton exchange membranes and catalyst materials.
2. Description of Related Art
A. Basic Principle of Invention
The basic principle underlying the multi-directional currents of the invention may be understood from FIGS. 1A–1B . FIG. 1A shows the situation when electrode currents i E1 and i E2 in electrodes E 1 and E 2 are initially reversed, creating EMF or voltage pulses, edges, waves, or spikes that travel from left to right in the top electrode E 1 and from right to left in the bottom electrode E 2 . The current i S between the electrodes flows from the top electrode E 1 to E 2 , but changes direction as the current i S follows the respective EMF pulses or voltage spikes as they propagate from left to right through electrode E 1 and from right to left through electrode E 2 . Eventually, as shown in FIG. 1B , the current flows from top right to bottom left, at which point the currents in the respective electrodes are again reversed to cause EMF or voltage pulses, waves, edges, or spikes to propagate in the opposite direction. As a result, the current i S can be caused to reciprocate or continuously change direction in an oscillating or cyclical manner within the current-carrying medium between the electrodes. If i E1 and i E2 are DC currents, the electrodes can be kept at a constant potential so that the net current direction remains constant even though the instantaneous current direction changes continuously or periodically, enabling the direction-changing current i S to be used in electrolytic processes that require direct current. Alternatively, i E1 , and i E2 may be alternating currents, pulsed DC currents, or polarity-reversing DC currents. In addition, a similar but smaller variation in the direction of current will occur if the direction-reversing conventional current is applied to just one of the electrodes and the second electrode has a relatively small area.
The invention may thus be characterized as a method and apparatus of generating multi-directional currents in a medium by reversing the direction of electron flow in at least one of a pair of electrodes. If the voltages applied to the electrodes are DC voltages, then the multi-directional currents have characteristics of DC currents, and if the voltages applied to the electrodes are two or three phase AC voltages, then the multi-directional currents have characteristics of AC currents. However, unlike conventional DC and AC currents, the currents generated by the method and apparatus of the invention move or rotate. If the electrodes are one-dimensional wires, then the currents rotate in two-directions. If the electrodes themselves move, or extend over two or three-dimensions, for example a plane or a curved plane, then the currents will move in three-dimensions.
B. Conventional Electric Currents
There are two types of conventional electrical currents and corresponding voltages, neither of which changes direction in the manner of the present invention. The first, direct current (DC), was already well known when Benjamin Franklin performed his famous kite experiment in 1752 to prove that lighting was a form of electricity, while the second, alternating current, came into widespread use after Nikola Tesla invented the first alternating current motor in 1888 (U.S. Pat. No. 555,190).
Both direct and alternating voltages can be applied to electrodes for the purpose of causing a current to flow through a medium between the electrodes. However, the voltages are conventionally applied across the electrodes so that the resulting inter-electrode current follows a fixed, albeit reversible, path between the electrodes, irrespective of the type of medium or geometry of the electrodes. This is clearly the case in systems having only a single terminal for each electrode, and in systems having multiple terminals but no switching circuit.
It is of course possible to periodically reverse the polarity of currents applied to the electrodes in such a system, and a number of systems have been proposed for doing so, including the systems disclosed in the patents discussed below. However, none of the previously proposed systems involves changing the direction of current in a single one, or both, of the electrodes so as to vary the direction of current flowing between the electrodes by other than 180°.
The invention in its broadest form consists of the above-described multi-directional currents, and apparatus and methods for generating the currents. However, an important aspect of the invention is the numerous applications in which the unique properties of the multi-directional currents may be exploited. These applications include, but are not limited to, the following:
C. Hydrogen Generation by Electrolysis of Water
One of the applications of the invention is electrolysis of water to generate hydrogen, or hydrogen and oxygen, for use in fuel cells and other essentially pollution-free hydrogen-driven power sources. This application is of particular importance because it offers a solution to the problem of generating, storing, and transporting the hydrogen.
Hydrogen fuel cells, in particular, have the potential to provide a completely non-polluting power source of electricity, not only for vehicles but also for electricity generation in general, but have been limited by lack of a safe distribution system for the hydrogen, and by the costs of generating the hydrogen in the first place. While it has long been known that hydrogen may be generated by applying a direct current to water, the rate of hydrogen generation is too low to provide a practical hydrogen source for mass distribution. As a result, hydrogen for mass consumption is currently produced from fossil fuels at relatively high energy costs relative to the energy value of the hydrogen produced. However, if sufficient hydrogen could be produced by water electrolysis to provide an on-board hydrogen generator for a vehicle or electric power plant, so as to generate just enough hydrogen to supply the fuel cells, then the need for a distribution system and hydrogen storage would be eliminated.
Power or propulsion systems that use water electrolysis in combination with hydrogen fuel cells to generate the hydrogen necessary to power the fuel cells are known as regenerative electrochemical cell or systems, an example of which is disclosed in U.S. Published Patent Application No. 2002/0051898. Despite their theoretical promise, however, similar systems have yet to offer a practical alternative to fossil fuels. It is believed that a regenerative system can only attain widespread acceptance if the efficiency of hydrogen production is increased. The multi-directional currents of the invention offer the potential for providing such an increase in water electrolysis efficiency.
The way that the invention increases water electrolysis efficiency is by using the applied electric current to not only pull the water molecules apart at the cathode, as in a conventional electrolysis system, but to add a shearing force that helps break apart the ionic bonds between the oxygen and hydrogen atoms. The effect is similar to separating a pair of magnets by sliding them perpendicularly rather than pulling them apart. In conventional electrolysis, the water molecules tend to align with the positive and negative electrodes in the manner illustrated in FIG. 2 , so that the ionic bonds are at a constant angle of 54.74° relative to the direction of current flow. This is not the optimal angle for breaking the ionic bonds and disassociating the hydrogen atoms from the oxygen atoms. In the set-up illustrated in FIG. 3 , on the other hand, the molecules are subject to a continuously changing current direction, which applies both tensile and shearing forces to the molecules, substantially increasing the rate of disassociation. In addition, the electrodes can be arranged in coils to add magnetic forces that further expedite disassociation.
It will be noted that the set-up illustrated in FIG. 2 does not reverse the polarities of the electrodes, which would only slow the electrolysis process due to energy lost in flipping the water molecules. The multi-directional currents are not alternating currents, but rather in this embodiment are direct currents. Systems that reverse the polarities of electrodes have previously been used in electrolysis, but the currents are uni-directional and the reversals are carried out at relatively long intervals so that the effect is that of a conventional DC current. The purpose of the reversals is to reduce scaling by switching between anodic and cathodic reactions at the respective electrodes. This can also be accomplished with the present invention, by reversing the polarities of the electrodes in addition to reversing current directions in the individual electrodes. Examples of electrolysis apparatus (though not necessarily a hydrogen generating water electrolysis apparatus) that reverse DC potential between two electrodes are disclosed in U.S. Pat. Nos. 6,258,250, 6,174,419, and 1,402,986, and in U.S. Published Patent Application No. 2002/0074237.
Periodic reversal of the polarities of electrodes has also been used in electrolytic water purification systems. The periodically reversed currents can be used to directly destroy bacteria as in U.S. Pat. No. 3,865,710, or to expedite the release of electrolytic reaction by-products such as metal ions, as disclosed in U.S. Pat. Nos. 6,241,861; 5,062,940; 4,908,109 (entitled “Electrolytic Purification System Utilizing Rapid Reverse Current Plating Electrodes”); U.S. Pat. Nos. 4,734,176; 4,525,253; and 3,654,119.
These systems are not to be confused with the system of the invention, which changes the direction of currents but does not necessarily change their polarity. However, the effects of the direction-reversing currents, and/or released ions, on bacteria and other micro-organisms can be utilized and even increased by the present invention, i.e., the currents of the present invention can be used not only for electrolysis of water to generate hydrogen, but also to purify the water. Unlike the currents disclosed in the water purification references, which cannot be used for hydrogen generation, the present invention combines generation of hydrogen with water purification so that, for example, a power plant that included hydrogen generation cells supplied with river water would also have the effect of cleaning the river water, serving as a source not only of electricity but also of potable water.
D. Charging of Nickel-Metal Hydride Foam Batteries
Although especially useful for water electrolysis, the present invention is not limited to a particular electrolyte, electrolytic process, or electrolytic cell configuration. In another application of the invention, the multi direction currents of the invention are applied to the electrodes of a battery containing an electrolyte. This application of the invention takes advantage of the reversing currents in the electrodes to reduce the wear and tear of friction and heat caused in conventional batteries by current moving from one post down the length of the electrode.
In the case of batteries containing nickel metal hydride, as disclosed in U.S. Pat. No. 6,413,670, additional advantages of using the method and apparatus of the invention to charge the battery an increase in the hydrogen generated during the charging process, which may be captured by utilizing the principles of the gas capture system described in copending U.S. patent application Ser. No. 10/314,987 filed on Dec. 10, 2002 by the present inventor now U.S. Pat. No. 6,890,410. Furthermore, the use of multi-directional currents may improve the ability of the foam to absorb hydrogen through the hydride substrate in a manner analogous to shaking of a screen to expedite passage of granular materials.
E. Capacitors
The apparatus and method of the invention can also be applied to capacitors and capacitive systems, which have similar fundamental problems of fast charging heat losses and discharge heat wear.
An example of capacitive systems to which the principles of the invention may be applied are the thrust generating systems disclosed in U.S. Pat. Nos. 6,317,310, 3,022,430, and 2,949,550, which use the electrostatic force between asymmetric capacitor plates to generate a thrust force. The EMF voltage spikes utilized by the present invention amplify the high voltage as the current changes direction to improve thrust performance. In addition, the magnetic field switching multi-directional high voltage currents may be computer controlled on the surface of the capacitor module's thrust plates or thrust tubes to change the direction and speed of the module, and the polarity of the currents may be controlled to change the direction of thrust. Thrust, pitch, roll, and yaw can be controlled by multiple such capacitor modules.
F. Cold Cathode Light and Plasma Generators
The principles of the invention are not limited to electrolyte materials, but may be applied to any medium capable of carrying charges between a pair of electrodes, including not only electrolytes, but also gases, gels, and semi-conductors. For example, when applied to a cold cathode light, reversing the current direction in the electrodes to change the direction of the excitation current between the electrodes will cause the ionized gas to produce more electrons, and thereby produce a brighter glow.
Similarly, in systems that generate plasma by passing a gas between electrodes, the multi-direction currents of the invention will increase the rate of plasma production relative to direct current systems, and those that use a single electrode polarity reversing switch applied to a single terminal on each of the electrodes of the plasma generator, as disclosed in U.S. Pat. No. 6,222,321.
G. Electro-Magnetic Devices
According to Lenz's law, a changing electrical current generates a magnetic flux having a magnitude that is proportional to the rate of change of the current. In the present invention, which utilizes reversing direct currents in the electrodes, the energy resulting from the above-described EMF or voltage pulses, edges, waves, or spikes can also be utilized to generate a corresponding magnetic field, which in turn can be used to drive a projectile in an electromagnetic gun, or a piston.
In addition, such systems can be made regenerative by capturing hydrogen generated during charging and using the hydrogen to power a fuel cell, which in turn charges a battery for accumulating energy to be supplied to the electrode coils when the weapon is fired or the piston is to be operated.
H. Computing Devices
By adding two inputs and outputs to the conventional electrolytic cell, the apparatus of the invention may also be used in logic circuits and computing devices. U.S. Pat. No. 3,172,083 discloses an electrolytic memory utilizing three electrodes, but each electrode only has a single input, and thus the resulting storage cell has no advantage over conventional silicon memory devices.
I. Medical Devices
The multi-directional currents of the invention may also be applied to a variety of medical devices, including x-ray machines and various devices for treating tissues by electrical currents and/or magnetic fields.
SUMMARY OF THE INVENTION
It is accordingly a first objective of the invention to provide an apparatus and method that utilizes electricity in a more efficient manner in order to conserve energy resources and protect the environment.
It is a second objective of the invention to provide an improved electrical current generating apparatus and method which accelerate electrolytic and cathodic processes, including generation of hydrogen.
It is a third objective of the invention to provide an improved electrical current generating apparatus and method capable of more efficiently sterilizing water.
It is a fourth objective of the invention to provide an improved electrical current generating apparatus and method capable of more efficiently charging a battery.
It is a fifth objective of the invention to provide an improved electromagnetic device capable of utilizing the counter-EMF generating upon reversal of an electric current.
It is a sixth objective of the invention to provide a multi-dimensional electrical current having the property of changing direction as it flows from one electrode to the other, with or without changes in polarity.
It is a seventh objective of the invention to provide a system and method for generating a direct current that changes current direction with at least two ground switching paths and two positive connections in a parallel switching relationship back and forth, in phase or out of phase.
It is an eighth objective of the invention to provide a direct current that changes directions while the polarity of the electrodes changes back and forth.
It is a ninth objective of the invention to provide an alternating current with a sine wave in a parallel relationship with earth ground or neutral which switches from one end to the other to control the direction of current from the ground or neutral.
These objectives are achieved, in accordance with the principles of a preferred embodiment of the invention, by providing an apparatus having at least two spaced electrodes, a current carrying medium between the electrodes, and at least two terminals at each end of each of the electrodes, for a total of at least four terminals, to which a direction-reversing direct or alternating current is applied.
The electrodes may have a variety of shapes, including wires, coils, planar, or curved structures. The direction reversal may be effected by an electromechanical switching network, solid state, photonic or mechanical switches, and so forth, including the current reversing circuitry disclosed in the above-cited patents. In addition, the currents applied to the electrodes may include alternating as well as direct currents, the present invention being distinguished in that the current reversing circuitry is applied to opposite ends of at least one, and preferably each, of the two electrodes, so that reversal of the currents occurs within the electrodes, as opposed to within the current carrying medium between the electrodes (although, as described below, the direction of the multidirectional current within the current carrying medium may also be reversed by switching the polarity of the electrodes in addition to reversal of the current within the electrodes).
In the case of an electrolytic process, the multidirectional currents have the effect of substantially increasing the efficiency by which bonds in the electrolyte are broken, thereby providing an enhanced electrolysis method for producing hydrogen, oxygen, and other gases, and at the same can be arranged to purify the remaining electrolyte.
When the electrodes are in the form of coils, then a magnetic field is generated that may further accelerate certain electrolytic processes such as the generation of hydrogen, with or without using the multi-directional currents. While the advantages of multi-directional currents apply to coil-shaped electrodes, advantages may also be obtained by operating electrolytic cells and other devices with coil-shaped electrodes in DC, pulsed DC, reversing polarity, and AC modes, in addition to various multi-directional current modes.
The new types of currents and corresponding voltages can be used to power a new generation of batteries, capacitors, motors, light bulbs, and plasma generators, as well as for hydrogen and oxygen generation, and further may be applied to applications ranging from electroplating of metals and plastics to transportation, to name just a few of the potential applications. In the field of medicine, the currents can be used in x-ray machines, to destroy cancer cells by placing a patient inside a coil to which the currents are supplied at frequencies known to kill cancer cells without affecting non-cancerous tissue, and in other devices that involve application of electrical currents and/or magnetic fields to tissues. DNA electrophoresis can be performed by using ADC instead of DC by running DNA gel samples from both ends of the gel plate instead of one. 46% of the planet's population doesn't have electricity or fresh drinking water due to the cost of infrastructure required to supply power lines and water connections. The new clean and cheap voltages (which may be referred to as SULLY VOLTAGES™ after the Inventor, John Sullivan) will revolutionize third world countries by supplying cheap power and fresh drinking water without petroleum based fuel oil.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1A and 1B are schematic diagrams illustrating the manner in which a multidirectional current is generated according to the principles of the invention.
FIG. 2 is a schematic diagram of a conventional electrolysis cell.
FIG. 3 is a schematic diagram showing the operation of an electrolysis cell constructed in accordance with the principles of the present invention.
FIG. 4 is a schematic diagram showing the construction of a water electrolysis system that includes an electrolysis cell of the type illustrated in FIGS. 1A , 1 B, and 3 .
FIG. 5 is a timing diagram for the electrolysis system of FIG. 4 .
FIGS. 6–9 are schematic diagrams showing variations of the electrolysis cell illustrated in FIG. 4 .
FIG. 10 is a schematic diagram of a lighting element constructed in accordance with the principles of the invention.
FIGS. 11–13 show further variations of the electrolysis cell illustrated in FIG. 4 .
FIG. 14 is a timing diagram for the polarity-reversing electrolysis cell illustrated in FIG. 13 .
FIGS. 15–17 are schematic diagrams of various applications of the principles of the invention to the charging of batteries.
FIG. 18 is a timing diagram for the battery charge/discharge circuit of FIG. 17 .
FIGS. 19 and 20 are schematic diagrams of various applications of the principles of the invention to electromagnetic devices.
FIG. 21 is a schematic diagram of a cold cathode light system that utilizes the principles of the invention.
FIG. 22 is a schematic diagram of a plasma generator that utilizes the principles of the invention.
FIG. 23 is a schematic diagram illustrating application of the invention to a three electrode device.
FIG. 24 , which appears with FIG. 15 , and FIG. 25 are schematic diagrams of jelly roll versions of the electrolysis cells and/or batteries of the preferred embodiments.
FIG. 26 is a schematic diagram of a multiple electrode electrolysis cell.
FIG. 27 is an alternative timing diagram for the switching circuit illustrated in FIG. 4 .
FIG. 28 shows a variation of the arrangement schematically illustrated in FIGS. 1A and 1B , with additional switches and center taps for controlling the electromagnetic pulses in each electrode.
FIG. 29 is a cross-sectional view of two capacitors connected in series according to the principles of the invention.
FIG. 30 is a schematic diagram of two capacitors connected in parallel according to the principles of the invention.
FIG. 31 is a schematic diagram of a jelly roll capacitor configuration.
FIG. 32 is a perspective view of a capacitive thrust module constructed in accordance with the principles of the invention.
FIG. 33 is a plan view of the thrust module of FIG. 33 , illustrating the manner in which currents are controlled on the surface of one of the capacitor plates.
FIG. 34 is a cross-sectional view of a capacitive thrust module with an EMF capture coil.
FIG. 35 is a schematic diagram of an RLC circuit that charges when current flow is changed according to the principles of the invention.
FIG. 36 is a schematic diagram of a transmitter circuit with a tuned capacitor in which the current change amplifies the signal on both the plus and minus side of the circuit according to the principles of the invention.
FIG. 37 is a schematic diagram of a capacitor circuit in which the capacitance is controlled by currents in the electrolyte.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 4 illustrates an apparatus 1 which utilizes the principles of the invention to generate hydrogen and oxygen according to a first preferred embodiment of the invention. The apparatus 1 includes a tank 2 , water supply 3 , two electrical conductors 4 , 5 which form electrodes corresponding to electrodes E 1 and E 2 of FIGS. 1A and 1B for an electrolysis process, two conventional DC current sources 6 , 7 , and four switches SW 1 –SW 4 .
The water 8 in this example may include a catalyst such as KOH, as is conventional, although the increased efficiency of the electrolysis process of the invention makes it possible to use ordinary tap water or water from rivers and lakes without adding additional catalysts.
When switches SW 1 and SW 4 are closed and switches SW 2 and SW 3 are open, current flows from the positive electrode of power source 6 through switch SW 1 to conductor 4 , and then is carried by ions in the water 8 to conductor 5 , switch SW 4 , and the negative electrode of power source 7 . On the other hand, when switches SW 2 and SW 3 are closed and switches SW 1 and SW 4 are open, current flows from the positive electrode of source 7 through switch SW 3 into conductor 4 , and then is carried by ions in the water to conductor 5 , through switch SW 2 , to the negative terminal of power source 6 .
It will be appreciated that there may be a delay between opening of switch pairs SW 1 ,SW 4 and closure of switch pairs SW 2 ,SW 3 , although simultaneous switching is preferred. In addition, the power sources and switching circuitry is not limited to the illustrated batteries and switches, but rather may include any power sources and switching circuitry capable of effecting reversal of currents within the individual electrodes, including solid state switching circuitry and rectified AC power sources. The illustrated diodes 14 and 15 are not essential, and may be omitted or replaced by appropriate voltage regulation, filtering, or other circuit elements.
The ionic current passing through the water from conductor 4 to conductor 5 causes disassociation of hydrogen from oxygen in the water according to the well-known process of electrolysis. Optionally, the oxygen (O 2 ) produced in the process may be trapped by a membrane 10 encircling conductor 4 for collection through an outlet 11 and storage tank 12 , while hydrogen (H 2 ) is collected via an outlet 13 .
Variations in the direction of current passing through the water subjects the individual water molecules to shearing as well as tensile forces that expedite disassociation. In addition, different types of microorganisms are known to be sensitive to specific frequencies of electrical current, and therefore switching of the applied conventional currents at an appropriate frequency can have the effect of purifying the water remaining in the tank.
FIG. 5 shows the electrical currents present at various places in the apparatus of FIG. 4 . Timing of the switches may be controlled by a clock pulse illustrated in FIG. 4( a ). FIGS. 4( b ) to 4 ( e ) show the currents through switches SW 1 –SW 4 , respectively, while FIGS. 2( f ) and 2 ( g ) show the respective voltages at terminals E 1 and E 2 between switches SW 1 ,SW 4 and conductors 4 , 5 .
FIG. 6 shows a variation of the electrolytic hydrogen generator of FIG. 4 , in which the electrodes E 1 and E 2 are in the form of coils 16 , 17 . According to the well-known right hand rule, a magnetic field is generated in the coils 16 , 17 having a direction corresponding to the direction of current input to the coils. These fields shift position as they follow the incoming and reversing currents, creating a magnetic vortex that further accelerates disassociation of the water molecules. As illustrated in FIG. 6 , only hydrogen (H 2 ) is collected, although of course oxygen may also be collected as necessary, for example by “bagging” one of both of the electrodes 16 , 17 in a membrane 10 , in the manner illustrated in FIG. 4 , or the electrodes may otherwise be separated by a porous barrier to prevent arcing and trap products of the anodic reaction. Alternatively, the coils 16 ′, 17 ′ may be coaxially arranged, as illustrated in FIG. 7 , so that the net magnetic fields will cancel out, even though the instantaneous magnetic fields will still change.
It will be appreciated that the magnetic fields generated in the embodiments of FIGS. 6 and 7 have advantages apart from the advantages resulting from reversal of the currents in the electrodes, and therefore the apparatus of this is embodiment is not intended to be limited to multi-directional current generation. Instead, it is within the scope of the invention to apply DC, pulsed DC, reversing polarity, and AC voltages, as well as various multi-directional currents, to the coiled electrodes, and to cause the magnetic fields to synchronously or non-synchronously reverse polarities and/or directions, with the fields either reinforcing each other or cancelling out.
The magnetic fields generated by the coaxial coil electrolytic cell apparatus of FIG. 7 are capable of generating a substantial gas flow even when the medium between the coils 16 ′, 17 ′ is ordinary tap or distilled water, at coil spacings of between 0.005 and 0.500 inches, and preferably between 0.050 and 0.200 inches. When a catalyst such as potassium hydroxide (KOH) is added to the water, the spacing between the two coils 16 ′, 17 ′ may be between 0.032 and 6.000 inches, with the preferred spacing still being between 0.050 and 0.200 inches. In addition, the gap or spacing between adjacent coils 16 ′, 17 ′ of each electrode may be between 0.001 and 0.500 inches, with a preferred gap of 0.032 to 0.100 inches.
As in the non-coiled embodiments, the electrolytic reaction rate may be increased still further by applying light to the apparatus, so that the energy of the photons adds to the energy supplied by the electric fields between the electrodes and the magnetic fields within the electrodes. Either or both of the electrodes may be enclosed within a membrane bag, sack, or tubing, as also discussed above, and currents and/or fields may further be arranged to kill microorganisms.
FIG. 8 illustrates a variation of the switching system illustrated in FIG. 4 , in which a single battery or cell is used to supply electricity to the two electrodes E 1 and E 2 . In this system, closed switches SW 5 and SW 7 cause current in electrodes E 1 and E 2 to flow in a first direction when switches SW 6 and SW 8 are open, while closed switches SW 6 and SW 8 and correspondingly open switches SW 5 and SW 7 cause current to reverse and flow in an opposite direction. The reversal affects the shearing and tensile force separation of the water molecules in the manner earlier described with respect to FIG. 3 .
FIG. 9 illustrates a variation of the system of FIG. 7 in which AC current is applied to the at least one of the electrodes, and the direction of the AC current is reversed by alternately opening and closing the switches SW 1 ,SW 4 and SW 2 ,SW 3 .
FIG. 10 illustrates a lighting system in which the electrolyte is replaced by a material 20 that emits light when excited by a reversing current generated by alternately opening and closing the switches SW 1 ,SW 4 and SW 2 ,SW 3 .
Those skilled in the art will appreciate that the multidirectional current generating apparatus of FIGS. 4–10 may also be connected together in various combinations. For example, FIG. 11 illustrates two electrolytic cells 22 and 23 , each corresponding to the cell illustrated in FIG. 8 , connected in parallel. FIG. 12 illustrates the same two electrolytic cells connected in series. In each case the current is reversed by alternately opening and closing the switches SW 1 ,SW 4 and SW 2 ,SW 3 .
FIG. 13 illustrates an apparatus corresponding to that of FIG. 4 , but with additional polarity reversal of the two electrodes 4 , 5 . In the apparatus of FIG. 13 , switches SW 5 to SW 8 effect current reversal within the electrodes to generate a multidirectional current in the current carrying medium 8 , illustrated as water, while switches SW 1 to SW 4 reverse the polarity of electrode 4 and switches SW 9 to SW 12 reverse the polarity of electrode 5 . A corresponding timing diagram is illustrated in FIGS. 14( a ) to 14 ( o ).
FIG. 15 shows a charging circuit for an electrolytic battery 25 , which may be a nickel metal hydride battery of the type described in U.S. Pat. No. 6,413,670, but which includes a current reversal circuit of the type illustrated in FIG. 4 for reversing the direction of currents in the positive electrodes 26 and the negative electrodes 27 . The illustrated current reversal prevents asymmetric accumulation of ions on the electrodes, and therefore reduces wear caused by excessive heating, while the multi-directional current in the electrolyte reduces buildup of electrolytic reactants on the terminals. In addition, in the case of a nickel metal hydride battery, the current reversal facilitates absorption of hydrogen by the nickel material.
FIG. 16 illustrates an alternate switching circuit for batteries of the type illustrated in FIG. 15 , with the electrodes 28 – 30 connected in series.
Operation of the battery can be further improved by adding a current reversing discharge circuit to the current reversing charging circuit to prevent excess wear due to asymmetric discharge currents. As illustrated in FIG. 17 , discharge of a battery 32 is synchronized to the phase of a motor 33 by means of a synchronizer control 34 and motor commutating switches SWA to SWD. In this embodiment, switches SW 1 to SW 4 operate in the same manner as the corresponding switches of the water electrolysis system or hydrogen generator illustrated in FIG. 4 . A timing diagram for the synchronized charge and discharge of the battery of FIG. 17 is included in FIGS. 18( a ) to 18 ( j ).
It will be appreciated that the principles of the invention may be applied to a variety of different types of batteries, including hydrogen batteries as well as the illustrated nickel metal hydride battery, and the invention is not to be limited to a particular type of battery.
FIGS. 19 and 20 illustrate application of the principles of the invention to an electromagnetic device such as an electromagnetic projectile launcher 40 ( FIG. 19 ) or a piston driver 50 ( FIG. 20 ). In each of these devices, two electrodes 41 and 42 are arranged coaxially and oppositely wound to generate a magnetic flux in a common direction. The reversing DC currents are supplied to the coils by a battery 43 of the type illustrated in FIG. 15 through switches SW 1 to SW 4 , with oxygen and hydrogen being generated by electrolysis and separated by a membrane 44 . The oxygen (O 2 ) and hydrogen (H 2 ) are discharged via respective outlets 45 and 46 to a fuel cell 47 which generates electricity for use in charging the battery 43 through charging circuit 48 when the devices are in a standby state, and for driving the projectile (PROJECTILE) shown in FIG. 19 or piston ( 50 ) shown in FIG. 20 when the devices are active.
FIG. 21 shows details of a cold cathode light 52 having electrodes 53 – 56 alternately supplied with a high voltage AC current through switches SW 1 to SW 4 . In this application, the current in the lighting medium (GAS) switches direction because it alternately flows between electrode pairs 53 , 55 and 54 , 56 rather than because of current reversals within the electrodes.
FIG. 22 shows a plasma generator having a switching circuit identical to that shown in FIG. 4 , but in which the current carrying medium is a gas, the current reversals in the electrodes 58 and 59 generating a multidirectional current in the gas that increases the rate and uniformity of plasma generation.
In addition to the numerous different applications described above, the configuration and number of the electrodes may be varied in a variety of ways without departing from the scope of the invention. For example, more than two electrodes may be included, such as the three electrodes 60 – 62 shown in FIG. 23 , or the electrodes may be interleaved as illustrated in FIGS. 24 and 25 . FIG. 25 shows the additional feature of an external light source 64 for further increasing the rate of gas production, as described in US Patent Published Patent Application No. 2002/0060161 (entitled Photo-Assisted Electrolysis) in an electrolysis cell 65 that can be used as part of, or to enhance, a regenerative solar electricity generating system, and that uses planar coiled electrodes 66 and 67 arranged in a jelly roll configuration. FIG. 26 illustrates an alternate gas separation system in a multiple electrode electrolysis cell corresponding to the one illustrated in the above cited copending patent application, and that uses multiple membranes 68 housing or bagging alternate electrodes.
The principles of the invention may also be applied to various capacitive systems, as illustrated in FIGS. 29–37 , by using a material or structure 70 that permits passage of ions as a dielectric separator between the electrodes E 1 ,E 2 of the capacitor. For example, as illustrated in FIGS. 29 and 30 , the direction of currents between the two electrodes E 1 ,E 2 of a single capacitor, or the respective electrodes E 1 ,E 2 of multiple capacitors connected in series ( FIG. 29 ) or parallel ( FIG. 30 ), may be reversed using four or more switches SW 1 –SW 8 in the same manner as described above in connection with FIG. 4 . By symmetrically charging and discharging the capacitors, asymmetric heat build-up in the electrodes is prevented, improving performance and extending the life of the capacitors.
The capacitors to which the principles of the invention are applied may take, of course, a variety of forms, and are not limited to a particular electrode geometric or specific electrode or dielectric materials. FIG. 31 , for example, shows a jelly roll capacitor configuration similar to the jelly roll configuration of the electrodes in the electrolytic cell of FIG. 25 .
As especially advantageous application of the principles of the invention to capacitive systems is the thrust module illustrated in FIGS. 32 and 33 , which improves upon the thrust module described in U.S. Pat. No. 6,317,310 by varying the direction of currents applied to high voltage electrode plate 72 , thereby enabling the thrust direction to be varied. In this configuration, the negative electrode 74 has switch terminals at each end, in a manner similar to the other embodiments of the invention, but the positive electrodes have additional switch terminals SW 1 –SW 8 so as to enable the direction of current in the dielectric 76 to not only be reversed, but also to change angular position and thereby the thrust angle, depending on which pairs of switches are operated.
FIG. 34 illustrates a variation of the thrust module of FIGS. 32 and 33 , in which current is supplied by a high voltage source 84 to electrodes 80 and 81 , which coaxially surround dielectric material 83 , through current-direction reversing switches SW 1 –SW 4 , and the resulting EMF pulses in electrodes 80 and 81 are captured by a coil 85 to produce a voltage when the current changes direction, thereby generating magnetic fields to create a thrust force.
Capacitors or capacitor circuits of the type illustrated in FIGS. 29–33 may also be used in a variety of other capacitor circuits, such as the ones illustrated in FIGS. 35–37 . FIG. 35 shows an RLC circuit that charges when the direction of current is changed using switches SW 1 and SW 4 , while FIG. 36 shows a tuner circuit for a transmitter in which the current change amplifies the transmitted signal on both the plus and minus sides of the circuit, and FIG. 37 shows an alternative capacitor construction and circuit in which the capacitance is controlled by the adjusted electrolyte 90 in which the capacitor electrodes 91 , 92 are immersed.
Those skilled in the art will appreciate that in any of the above-described embodiments and implementations of the invention, both the manner in which the current is caused to alternate direction in the electrodes, and the timing and magnitude of the EMF pulses, can be varied according to the principles of the invention. For example, FIGS. 27( a )– 27 ( f ) are timing diagrams of a variation of the preferred switching system in which opening and closing of switches SW 1 and SW 4 is delayed relative to closing and opening of switches SW 2 and SW 3 . On the other hand, FIG. 28 illustrates a variation of the apparatus illustrated in FIG. 3 , in which center taps and switches SW 19 and SW 20 are added to enable manipulation or softening of the EMF pulses in the electrodes.
In addition to the illustrated applications, other potential applications of the principles of the invention are as follows:
The electrolytic cell illustrated in FIG. 4 or an analogous switched semiconductor device could also be used as a type of computing device in which sensors monitor the direction of current flow. Instead of using Boolean logic, the computer would use the current flow sensors to sense directions, with zero current to 0, and different current directions to +1, +2, +3, and so forth. In addition, the transistors that change the direction of the current may be part of a ladder logic equation and for setting the timing and logic expression, for example by performing a flip flop function timed with current flow.
Another possible application is to use the currents to reduce radioactive waste of spent nuclear fuel by attaching the electron orbits of spent fuel in a multi-dimensional oscillating electric field, or a polarity reversing multi-dimensional electric field.
It will be appreciated that one can build an electromagnetic generator that will produce multi-directional currents and corresponding voltages, rather than converting the currents or voltages from another DC or AC voltage. Also, mechanical cam switching can create multi-directional currents and corresponding voltages, and one can similarly build motor that will run on new the voltages.
Finally, yet another possible application of the invention is to enhance dehydration of a porous material using electro-osmosis as described in U.S. Pat. Nos. 6,117,295 and 6,372,109.
Having thus described a preferred embodiment of the invention in sufficient detail to enable those skilled in the art to make and use the invention, it will nevertheless be appreciated that numerous variations and modifications of the illustrated embodiment may be made without departing from the spirit of the invention, and it is intended that the invention not be limited by the above description or accompanying drawings, but that it be defined solely in accordance with the appended claims.
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Multi-directional currents are generated in a medium by cyclically reversing the direction of a conventional current applied to at least one of at least two electrodes so that an electromotive force (EMF) pulse travels from side of the electrode to the other, changing the direction of current in the medium. The multi-directional currents may be used to accelerate electrolytic processes such as generation of hydrogen by water electrolysis, to sterilize water for drinking, to supply charging current to a battery or capacitor, including a capacitive thrust module, in a way that extends the life and/or improves the performance of the battery or capacitor, to increase the range of an electromagnetic projectile launcher, and to increase the light output of a cold cathode light tube, to name just a few of the potential applications for the multi-directional currents.
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[0001] If an Application Data Sheet (“ADS”) has been filed on the filing date of this application, it is incorporated by reference herein. Any applications claimed on the ADS for priority under 35 U.S.C. §§119, 120, 121, or 365(c), and any and all parent, grandparent, great-grandparent, etc., applications of such applications, are also incorporated by reference, including any priority claims made in those applications and any material incorporated by reference, to the extent such subject matter is not inconsistent herewith.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002] The present application claims the benefit of the earliest available effective filing date(s) from the following listed application(s) (the “Priority Applications”), if any, listed below (e.g., claims earliest available priority dates for other than provisional patent applications or claims benefits under 35 U.S.C. §119(e) for provisional patent applications, for any and all parent, grandparent, great-grandparent, etc., applications of the Priority Application(s)).
PRIORITY APPLICATIONS
[0003] U.S. patent application Ser. No. 13/483,970 entitled “Bicycle Bag,” filed on May 30, 2012, and U.S. Provisional Patent Application Ser. No. 61/492,183 entitled “Bicycle Bag,” filed on Jun. 1, 2011.
RELATED APPLICATIONS
[0004] If the listings of applications provided herein are inconsistent with the listings provided via an ADS, it is the intent of the Applicants to claim priority to each application that appears in the Priority Applications section of the ADS and to each application that appears in the Priority Applications section of this application.
[0005] All subject matter of the Priority Applications and the Related Applications and of any and all parent, grandparent, great-grandparent, etc., applications of the Priority Applications and the Related Applications, including any priority claims, is incorporated herein by reference to the extent such subject matter is not inconsistent herewith.
TECHNICAL FIELD
[0006] This disclosure relates to a bicycle bag and, in particular, to a bicycle bag that provides protection from the elements while the bike with bicycle bag are on a rack, and that can be used with a large variety of different bicycle and rack types.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] Additional aspects and advantages will be apparent from the following detailed description of preferred embodiments, which proceeds with reference to the accompanying drawings, in which:
[0008] FIG. 1A depicts an exemplary tray-type bicycle rack;
[0009] FIG. 1B depicts another exemplary tray-type bicycle rack;
[0010] FIG. 1C depicts an exemplary post-type bicycle rack;
[0011] FIG. 1D depicts an exemplary fork-type bicycle rack;
[0012] FIG. 2 depicts one embodiment of a bicycle bag; and
[0013] FIG. 3 depicts another embodiment of a bicycle bag.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0014] When a bicycle is secured to a rack the bicycle can become dirty or damaged due to exposure to the elements, road debris, vandalism, theft, and the like. As used herein a “rack” refers to any mechanism for securing a bicycle including, but not limited to: a vehicle rack configured to secure one or more bicycles to a vehicle for transport, a storage rack to storing a bicycle, a parking rack for bicycle storage, or the like. Bicycle covers or (bicycle “bags”) can be used to reduce this exposure. However, most existing bicycle bags do not provide sufficient protection. Moreover, bicycle bags that attempt to provide additional protection by covering the bicycle while in transit are often incompatible with certain vehicle rack systems, making their use dangerous and impractical. Moreover, these bags can be incompatible with certain bicycle types or frame configurations and/or may prevent bicycles from being “packed together” for transport. In some cases, when a bicycle is mounted on a vehicle rack, the bicycle (or bicycle bag) may obscure portions of the lighting system of the vehicle, such as the brake lights, turn signals, backup lights, and the like.
[0015] The bicycle bag disclosed herein addresses these and other shortcomings. The disclosed bicycle bag provides full coverage for a bicycle while on a rack. As used herein “full coverage” refers to a bicycle being fully enclosed by a bag, such that the bicycle is protected from outside elements, such as moisture, road debris, or the like. Accordingly, “full coverage” refers to a bicycle being fully enclosed within material of the bicycle bag, with no portions of the bicycle protruding therefrom. In some embodiments, the bicycle bag includes resealable openings configured to allow the bicycle bag to be used with a large variety of different rack types. The openings may be adapted such that the bicycle is protected whether or not the openings are in use. The disclosed bicycle bag may include pockets adapted to receive a lighting system, which may be used when the bicycle bag obscures the lighting system of the vehicle.
[0016] Various embodiments of a bicycle bag are disclosed herein. The disclosed bicycle bags provide advantages over existing bags. The features described with respect to the various embodiments may be combined in any suitable fashion.
[0017] The bicycle bag disclosed herein may be configured to allow a bicycle enclosed therein to be secured to a plurality of different rack types and/or securing mechanisms, which may include, but are not limited to: a tray-type rack, a post-type rack, a fork rack, bicycle straps, J-hooks, arm clamps, or the like.
[0018] FIG. 1A depicts an exemplary tray-type bicycle rack 170 . The rack 170 may comprise a J-bar to secure a wheel of a bicycle and one or more wheel trays. The one or more wheel trays may comprise respective straps for securing bicycle wheels thereto. FIG. 1B depicts another exemplary tray-type rack. The wheel tray of the rack 172 may comprise one or more wheel straps for securing a bicycle to the tray. The rack 172 may comprise a stabilizer bar configured to secure a bicycle in an upright position. The arm clamp may be configured to releasably secure one or more frame members of a bicycle (e.g., the downtube of a bicycle). As shown in FIG. 1B , the arm clamp may be configured to secure a bicycle in an upright position on the rack 172 . FIG. 1C depicts an exemplary post-type rack 174 . The rack 174 comprises one or more posts to which a bicycle frame may be secured. The one or more posts may comprise respective straps for securing a bicycle thereto. FIG. 1D depicts an exemplary fork-type rack 176 . The rack 176 may comprise a wheel tray having one or more straps to secure a bicycle wheel thereto. The rack 176 may further comprise a fork receptacle for securing a bicycle frame.
[0019] FIG. 2 depicts one embodiment of a bicycle bag 200 configured to allow a bicycle enclosed therein to be secured to a plurality of different rack types. The bicycle bag 200 may be constructed of any suitable material including, but not limited to: canvas, Kevlar®, neoprene, nylon, polyester, plastic, rigid plastic, metal, or the like, and/or combinations of different materials. The bag 200 (or portions thereof) may be formed from materials that are resistant to the elements. For example, the bag 200 may be formed from materials that provide protection from moisture (e.g., water proofing), provide ballistic protection from high-velocity road debris, are tamper resistant (e.g., include structural members, such as Kevlar® or metallic filaments or fibers, that resist cutting or tearing), or the like. In some embodiments, portions of the bag 200 (and/or the openings 203 and 204 therein) may be formed from flexible materials capable of adapting to different bicycle 201 and/or rack configurations. For example, the materials forming the opening 203 and/or resealable closure 243 thereof (discussed below) may be capable of expanding and/or deforming to adapt to different rack and/or bicycle 201 types. The flexible portions may be configured to allow the bag 200 to enclose bicycles 101 of different sizes and/or types.
[0020] As illustrated in FIG. 2 , bottom portions 211 and 212 of the bag 200 may be configured to generally conform to the shape of a bicycle 201 disposed therein. For example, the portion 211 may be configured to conform to the curvature of the front wheel 221 and the portion 212 may be configured to conform to the curvature of the rear wheel 222 . The portions 211 and 212 may be configured to allow the bag 200 to be used with bicycle racks that secure the bicycle 201 using curved wheel trays, such as the tray-type bicycle racks 170 , 172 , and/or 176 . The curvature of the bottom portions 211 and 212 of the bag 200 , allows a bicycle 201 disposed within the bag 200 to be secured by such a rack by, inter alia, securing the wheels 221 and 222 of the bicycle 201 within curved wheel trays of the rack.
[0021] The bag 200 may further comprise one or more resealable openings 204 in the wheel portions 211 and/or 212 . The openings 204 may be configured to allow a strap (or other securing mechanism) to pass through the bag 200 to secure one or more of the wheels 221 and/or 222 to, inter alia, a tray of a tray-type rack. The openings 204 may allow a securing mechanism to pass through the bag 200 and bicycle wheel 221 / 222 when the bicycle 201 is in the bicycle bag 200 . The openings 204 may comprise respective resealable closures 224 , which allow the bicycle 201 to be placed within the bag 200 and/or removed from the bag 200 (e.g., by disengaging the resealable closures 224 of the openings 204 ). The resealable closure 224 may comprise any suitable mechanism including, but not limited to: VELCRO®, a zipper, fastening straps, buttons, or the like. The resealable closure 224 may be configured to protect the bicycle 201 from the elements (e.g., moisture, debris, etc.). The openings 204 (and resealable closures 224 ) may be configured to avoid impinging on structural elements (e.g., spokes) of the bicycle 201 . Accordingly, in alternative embodiments, the openings may be narrowed and/or oriented vertically (along the radius of the wheels 221 and/or 222 ) so that the openings 204 may accept a securing member of a rack, while minimizing the chance of the openings impinging on wheel spokes or other components of the bicycle 201 . In some embodiments, the openings 204 may not be resealable, but may comprise one or more gaskets, flaps, elastics, or the like, that are configured to protect the interior portion of the bag 200 from the elements.
[0022] The bag 200 may further comprise resealable openings 205 disposed near the top portions 213 and 214 of the bag 200 . The resealable openings 205 may comprise respective resealable closures (not shown) configured to selectively open and/or seal the openings 205 . The openings 205 may be used to secure the bicycle 201 (and bag 200 ) to an upper portion of a rack (e.g., an over the wheel rack). As depicted in FIG. 2 , the openings 205 may be configured to prevent impinging on the structural components of the bicycle 201 (e.g., the wheels 221 , 222 and/or the spokes thereof).
[0023] In some embodiments, the bag 200 comprises a resealable opening 203 disposed near the center of the bag 200 . The opening 203 may be configured to create an opening within a diamond portion 203 of the bicycle 201 frame (under a top-tube of and/or above a down tube of the bicycle 201 ). The resealable opening 203 may be configured to allow the bicycle 201 to be secured to a post-type rack (e.g., a rack that secures a frame of the bicycle 201 to one or more posts or the like, such as the bicycle rack 174 ). For example, the opening 203 may be configured to provide for passing one or more posts of a post-type rack through the bicycle 201 within the bicycle bag 200 , such that the bicycle 201 may be secured thereto.
[0024] The opening 203 may be opened by disengaging the resealable closure 243 , which allows the bicycle 201 to be placed within the bag 200 and/or removed from the bag 200 . The resealable closure 243 may comprise any suitable mechanism including, but not limited to: VELCRO®, a zipper, fastening straps, buttons, or the like. The resealable closure 243 may be configured to prevent the elements (e.g., moisture, debris, etc.), from entering the interior of the bag 200 . The resealable closure 243 may be disengaged (e.g., opened) to allow the bicycle 201 to be placed within the bag 200 (or removed therefrom). The resealable closure 243 may re-sealed when the bag 200 is used for transport. In some embodiments, the opening 204 may not be resealable, and may comprise one or more gaskets, flaps, elastics, or the like, to protect the interior of the bag 200 from the elements.
[0025] In some embodiments, a top portions 213 and 214 of the bag 200 are configured to conform to the top portion of each wheel 221 and 222 . The top portions 213 and 214 allow the bicycle 201 (within the bag 200 ) to be secured to a “J-shaped” rack that secures the bicycle 201 using one or more “over-the wheel” J-shaped members, such as the bicycle rack 172 of FIG. 1A . Similarly, the portions 213 and 214 may allow the bicycle 201 and bag 200 to be secured to conventional shaped bicycle parking racks.
[0026] Although a particular set of resealable openings 203 , 204 , and/or 205 are depicted herein, one of skill in the art would recognize that the bag 200 could be adapted to include additional openings configured to allow the bag 200 to be used with different rack types and/or different bicycle 201 configurations. Accordingly, the disclosure should not be read as limited to any particular set of openings. For example, in some embodiments, the bag 200 may include one or more openings (not shown) or tabs (not shown), which may be used to secure or lock the bag 200 to a rack (or other structure).
[0027] In some embodiments, the bag 200 comprises one or more pockets 230 . The pockets 230 may be integrated into the bag 200 itself and/or may be removably attached thereto. The pockets 230 may be configured to receive tail lights 232 . The tail lights 232 may comprise any suitable lighting mechanism including, but not limited to: brake lights, turn signals, backup lighting, etc. The tail lights may be secured within the pockets 230 without the need for special brackets or other mechanisms. Accordingly, in some embodiments, the pockets 230 include a securing member 234 or flaps adapted to secure a tail light 232 therein (e.g., a zipper closure, VELCRO®, or the like). An exterior facing portion of the pockets 230 may be formed from a transparent material to allow light from the tail lights 232 to emit therefrom.
[0028] The bag 200 may provide an electrical connection between the pockets 230 and an exterior portion of the bag 200 . For example, the bag 200 may include an electrical connection 236 configured to receive an electrical connection from a vehicle, such as a trailer hitch electrical connection or the like. The electrical connection 236 may be disposed on a lower portion of the bag 200 to be proximate to a hitch electrical connection of a vehicle. The electrical connection 236 may be electrically coupled to each of the one or more pockets 230 . Accordingly, each of the two or more pockets 230 may include an electrical connection (not shown) in electrical communication with the electrical connection 236 . The electrical coupling may be implemented using conductors embedded within material of the bag 200 , conductors in the interior of the bag 200 , conductors along the exterior of the bag 200 , or the like. In some embodiments, the bag 200 may also comprise an electrical coupling output (not shown) to connect two or more of the bags 200 electrically in serial.
[0029] The bag 200 may comprise a resealable closure (not shown) along a bottom portion of the bag 200 . The resealable closure may be selectively opened to allow a bicycle 201 to be placed within the bag 200 and/or removed therefrom. The resealable closure may comprise any suitable mechanism including, but not limited to: Velcro®, a zipper, buttons, or the like. The resealable closure may be configured to protect the bicycle 201 from the elements when closed. Accordingly, the resealable closure may be waterproof and/or tamper resistant. In some embodiments, the resealable closure may include a locking mechanism to prevent the resealable closure from being opened. Alternatively, or in addition, the bag 200 may comprise a resealable closure along the top portion of the bag 200 . The top-portion resealable closure may allow a bicycle 201 to be placed within (or removed) from the top portion of the bag 200 .
[0030] The bag 200 may further comprise a portion 250 configured to allow the pedals and/or crank of the bicycle 201 to rotate therein. The pedals and/or crank may rotate within an arc 252 within the bag 200 . Accordingly, the portion 250 may comprise a sufficient interior volume to accommodate various bicycle pedal and/or crank configurations. The rotation 252 of the pedals and/or crank may facilitate arranging two or more bicycles next to one another on a rack. For example, the pedals of the two or more bicycles may interfere with one another when oriented side-by-side in a rack. The rotation 252 of the bicycle 201 pedals and/or crank may allow the pedals to offset one another, allowing the bicycles to be placed in closer proximity.
[0031] As discussed above, the bag 200 may be formed from a material configured to provide protection from the elements while the bicycle 201 is transported on a vehicle. Accordingly, the bag 200 may be formed from waterproof material and/or material that provides ballistic protection (e.g., protection from high-velocity road debris).
[0032] FIG. 3 illustrates other aspects of a bicycle bag as disclosed herein. The bicycle bag 300 comprises a resealable opening 315 running along a top rear portion and bottom of the bag 300 . The resealable opening 315 may be configured to receive a bicycle into an interior portion of the bag 300 . As described above, portions of the bag 300 may be formed from deformable and/or flexible material, such as spandex, neoprene, or the like. In the FIG. 300 example, a handlebar compartment 360 , a top-tube portion 361 , and a seat portion 362 of the bag may be formed from a deformable material, which may allow the bag 300 to accommodate bicycles of different sizes and/or configurations. For example, the handlebar compartment 360 of the bag may be configured to receive handlebars of varying widths and/or heights. Similarly, the top tube portion 361 may be deformable to accommodate bicycles of varying lengths, and the seat portion 362 may be deformable to accommodate bicycles of varying height. The bicycle bag 300 may be provided in different sizes and/or configurations. For example, the bag 300 may be provided in small, medium, and/or large sizes to accommodate a large range of bicycles sizes (e.g., frame sizes from 40 to 64 cm). Similarly, the bag 300 may be provided with different handlebar compartment 360 types, including, but not limited to: a road bike compartment configured to receive road bike handlebars, a mountain bike compartment configured to receive wider mountain bike handle bars, and/or a cruiser compartment configured to receive wide bar types. In some embodiments, the handle bar compartment 360 may be removable and/or modular, such that the bag 300 may switch between road, mountain, and/or cruiser handler bar compartments. Alternatively, or in addition, the handle compartment 360 may comprise one or more straps, expansion sleeves, or the like, to allow a user to change the configuration of the handlebar compartment 300 (and/or other portions of the bag 300 ) to accommodate a particular size and/or style of bicycle.
[0033] As shown in FIG. 3 , the opening 103 may be provided in a diamond shape to fit a wide variety of post-type racks. The opening 203 may be resealable, as described above. The bag 300 may further comprise a seat-tube opening 306 configured to allow a rack to secure a seat tube of a bicycle within the bag 300 . A down-tube opening 307 may be configured to allow a rack to secure a down tube of a bicycle within the bag 300 . In some embodiments, the opening 204 may be configured to allow a fork of the bicycle to protrude from the bag 300 , such that the fork may be secured to a fork-type rack (e.g., rack 176 ).
[0034] As described above, bottom portions 211 and 212 of the wheel compartments 281 and 282 may be configured to conform to a contour of the wheels of the bicycle. Accordingly, the wheel compartments 281 and/or 282 may be configured to allow the wheels of the bicycle to be secured to a tray-type rack and/or be secured using a wheel slot or clamp (or similar mechanism). As shown in FIG. 3 , the wheel compartment 281 may be configured to allow a front portion 283 A and/or rear portion 284 A of the front wheel to be secured to a tray and/or wheel slot or clamp. The wheel compartment 282 may be configured to allow a front portion 283 B and/or read portion 284 B of the rear wheel to be secured to a tray and/or wheel slot or clamp. In addition, the openings 204 may be used to secure the front and/or rear wheels to various rack types, as described above.
[0035] Top portions 213 and 214 of the wheel compartments 281 and 282 may conform to top portions of the bicycle wheels. As such, the wheel compartments 281 and/or 282 may be configured to allow the bicycle to be secured to an over-the-wheel rack, a J-hook, or similar mechanism. The bag 300 may further comprise pockets 230 to receive lighting, a crank compartment 250 configured to allow a bicycle crank and/or pedals to rotate within the bag 300 , as described above.
[0036] It will be understood by those having skill in the art that changes may be made to the details of the above-described embodiments without departing from the underlying principles presented herein. For example, any suitable combination of various embodiments, or the features thereof, is contemplated.
[0037] Any methods disclosed herein comprise one or more steps or actions for performing the described method. The method steps and/or actions may be interchanged with one another. In other words, unless a specific order of steps or actions is required for proper operation of the embodiment, the order and/or use of specific steps and/or actions may be modified.
[0038] Reference throughout this specification to “an embodiment” or “the embodiment” means that a particular feature, structure or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the quoted phrases, or variations thereof, as recited throughout this specification are not necessarily all referring to the same embodiment.
[0039] Similarly, it should be appreciated that in the above description of embodiments, various features are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure. This method of disclosure, however, is not to be interpreted as reflecting an intention that any claim require more features than those expressly recited in that claim. Rather, as the following claims reflect, inventive aspects lie in a combination of fewer than all features of any single foregoing disclosed embodiment.
[0040] The claims following this Detailed Description are hereby expressly incorporated into this Detailed Description, with each claim standing on its own as a separate embodiment. This disclosure includes all permutations of the independent claims with their dependent claims. Recitation in the claims of the term “first” with respect to a feature or element does not necessarily imply the existence of a second or additional such feature or element. Elements specifically recited in means-plus-function format, if any, are intended to be construed in accordance with 35 U.S.C. §112 ¶6.
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A bicycle bag protects a bicycle while the bicycle is secured to a rack, such as a vehicle bicycle rack. The bicycle bag includes resealable openings configured to allow the bicycle (and bag) to be securely attached to a wide variety of different rack types. Additionally, because there is risk of obscuring the tail lights of a vehicle for rear-mount racks when a bicycle bag is on the bike and the bike on the rack, the bicycle bag includes pockets designed to support a tail-light system that can be connected to the vehicle to provide additional lighting and safety.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 60/651,144, filed Feb. 8, 2005, entitled “A Skag Having Angled Attachment Stud”. This provisional application is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to skags for snowmobile skis.
BACKGROUND OF THE PRESENT INVENTION
[0003] Snowmobile skis typically have an elongated removable steering skag (sometimes also called a wear-bar) carried on the underside (i.e. bottom surface) of the ski (and usually on the keel thereof when the underside of the ski has a keel). The skag acts to increase the bite of the ski on groomed trails, on hard-packed snow and in icy conditions when the ski is turned. The skag is also used to lengthen the life of the underside of the ski by being the contact point or wear point of the ski on the ground (as opposed the other usually plastic parts of the underside of the ski) when the ski is in contact with the ground or other hard surfaces (e.g. road surfaces).
[0004] Conventional skags are normally an elongated piece of metal such as a steel rod having a circular or square cross-section. One such prior art skag 10 is shown in FIGS. 1 and 2 . This prior art skag 10 has a front 12 and a rear 14 that are normally angled slightly upwardly from a middle 16 to avoid the skag digging into the ground during use. The skag 10 is placed under the snowmobile ski such that it runs longitudinally along the underside of the snowmobile ski. In use, when the ski is travelling straight ahead, the skag 10 produces very little drag. When the ski is turned, the skag 10 is turned and creates drag over the ground surface and enhances the turning of the snowmobile. For extremely icy conditions, the bottom of the skag 10 could be equipped with one or more sharp triangular carbides 18 which further enhance the drag created between the ice and the skag 10 , thus further increasing the turning capabilities of the snowmobile ski.
[0005] Conventionally, removable prior art skags such as the one shown in FIG. 1 are secured to the underside of a ski by using studs 20 . Studs 20 are fixed, preferably welded, to the skag and extend upwardly away from the skag perpendicular to the longitudinal axis of the skag. The studs 20 are normally threaded to accept a nut. In most cases, a skag will be equipped with two or more longitudinally spaced studs to prevent bending of the skag when encountering side forces. To secure the skag to the underside of the ski, the studs are passed upwardly through holes in the ski and each receives a nut on the top side of the ski such that when the nut is in threaded engagement with the stud, the ski is sandwiched between the skag.
[0006] Typically, the material chosen for mass produced studs is of a high quality in order create durable threads, while that of the rod need not be of such a high quality since it is not threaded. The two materials are welded together to form the skag. However, this normally causes the welds between each stud and the rod to become the weakest point of the skag. Because the studs are attached perpendicular to the rod, the studs and particularly the welding are under shear stress when the ski is in use. Under certain circumstances, such as when the snowmobile is traversing a paved road or railroad tracks, the shear stress may be very high. The diameter of the stud and the amount of welding applied around the contact between the stud and the rod must be sufficient to withstand these high amounts of shear stress. In some cases, the shear force is nonetheless too high and the rod may be completely sheared away from the skag. This is undesirable. In other cases, the amount of material required to prevent this from occurring undesirably increases the cost of the skag.
[0007] Further, in conventional skags at least one of the studs passes through the ski close to the ski leg of the snowmobile, making access to the nut cumbersome due to its proximity to the ski leg. This makes it difficult for the skag to be removed and for a new skag to be attached.
[0008] Additionally, with the conventional construction of having the studs of a conventional skag perpendicular to the rod, there is always a possibility that the skag could be fitted to the underside of the ski in the wrong orientation (i.e. backwards) if the studs are equally spaced over the length of the rod.
[0009] Thus, while the current design of conventional skags is sufficient to provide a removable skag that enhances the turning capabilities of a snowmobile ski, there exists a need to provide an improved skag.
STATEMENT OF THE INVENTION
[0010] It is therefore an object of the present invention to provide an improved skag for a snowmobile ski that ameliorates at least one, and preferably more, of the above-noted disadvantages with conventional skags.
[0011] In one aspect, the present invention provides a skag for use on an underside of a complimentary ski for a snowmobile, the skag comprising: a rod of material having a front and rear defined consistently with a forward direction of travel of the skag when the skag is secured to the ski and the ski is connected to the snowmobile; a first stud immovably extending away from the rod of material at a first angle towards the rear of the rod of material, the first angle being less than 90°, the first stud having threads for securing the skag to the ski; and a second stud immovably extending away from the rod of material, spaced-apart from the first stud, at a second angle opening towards the rear of the rod of material, the second angle being less than 90°, the second stud having threads for securing the skag to the ski.
[0012] In another aspect, the present invention provides a skag for use on an underside of a complimentary ski for a snowmobile, the skag comprising: a rod of material having a front and rear defined consistently with a forward direction of travel of the skag when the skag is secured to the ski and the ski is connected to the snowmobile; a first stud having a first stud axis, the first stud immovably extending away from the rod of material such that when the skag is secured to the ski and the ski is connected to the snowmobile and the snowmobile is steered straight on horizontal level ground a first angle opening away from the front of the rod of material formed between a projection of the first stud axis and the ground is less than 90°; and a second stud having a second stud axis, second stud immovably extending away from the rod of material such that when the skag is secured to the ski and the ski is connected to the snowmobile and the snowmobile is steered straight on horizontal level ground a second angle opening away from the front of the rod of material formed between a projection of the second stud axis and the ground is less than 90°, the second stud being spaced-apart from the first stud.
[0013] Having the studs angled with respect to the rod as described hereinabove is believed to offer an advantage over skags of the prior art design. The primary advantage is believed to be in relation to dealing with the shear stresses created at the contact point of the rod and each stud. In this respect, due to the angles between the studs and the rod, assuming studs of a constant cross-section, the area of the contact between the studs and the rod will be greater when the studs are angled than when they are at 90°. For example, when the studs are cylindrical and the rod is rectangular, the intersection between a straight cylinder and the face of the rectangle will be a circle, whereas the intersection between an angled cylinder (having the same diameter as the straight cylinder) is an ellipse. This ellipse will have a greater diameter and area than the circle. Thus, the angled cylinder will have an increased area over which welding can occur, thus increasing the overall weld strength, thereby increasing the amount of shear force that such weld can withstand.
[0014] Moreover, the studs, in the prior art construction, were primarily (and almost totally) under a shear force when contact with the ground occurs. Whereas with the present invention, due to having the studs at angles, the forces applied to the stud and the weld are broken up into two components, a shear force and an upward force that pushes the skag into the bottom of the ski. Because the force (of a similar magnitude to that of the prior art) is now broken up into two components, the shear force experienced by the welds of skags of the present invention is decreased. Although the stud will be now subjected to a different force, it is believed that it is better to distribute the forces over all the component (i.e. the stud) as will be discussed below than have it all directed in one form to one particular area.
[0015] Depending on the construction of the skag and the ski to which the skag will be attached, some embodiments of the present invention will have additional advantages. The most common is that skags of the present invention will not be able to be incorrectly installed on the skis in the wrong direction (i.e. front of the skag towards the rear of the ski), as the complimentary holes or slots that accept them on the skis will go only from underside frontward to topside rearward. Additionally, depending on the construction and arrangement of the other topside ski components (e.g. the ski-leg, the bridge, and the handle), it may be that the angling of the studs causes the portion thereof on the topside of the ski to be easier accessed.
[0016] It should be noted that a rod of a skag of the present invention may be made of any material suitable for its intended purpose; steel is preferred. Thus, the rod need be only an enlogated body suitable for placement on the underside of the base of the ski. It need not have any particular cross-section, nor even a constant cross-section across its length (i.e. its cross-section may vary in size and/or shape across its length). A constant square cross-section is preferred.
[0017] Similarly, a stud of the present invention may be made of any material suitable for its intended purpose; steel is also preferred. Thus, a stud need only be an elongated body suitable for extending through a complimentary hole in the ski and adapted to mate with a suitable fastener. It need not have any particular cross-section, nor even a constant cross-section across its length (i.e. its cross-section may vary in size and/or shape across its length). A cylinder, having a threaded exterior end its preferred.
[0018] The stud axis will be evident to a person skilled in the art from the shape of the stud itself, it is the central longitudinal axis of the stud. For instance, where the stud is cylindrical, the stud axis will be the longitudinal central axis of the cylinder. Where the stud is a quadrilateral, the stud axis will be formed by the intersection of the planes defined by opposite corners. The same is true for the rod.
[0019] The studs extend immovably away from the rod; i.e. the studs cannot pivot about their contact point with the rod. Thus, an angle described hereinabove for any one given stud for any one given skag is not variable. This immovability between the stud and the rod ensures that the skag is constantly being pushed toward the underside of the ski due to the contact between angled hole and the angled stud. This is desirable since the surface area of the ski in contact with the rod is large and can withstand higher forces when compared with the shear forces that the weld and the stud can withstand. In a conventional skag, the welding and the studs are under solely shear force because other than the tension created by the nut (and the weight of the snowmobile on the ski), in use the skag is not constantly being pushed up towards the underside surface of the ski but rather is being pushed purely rearward. In a case where the studs were pivotally connected to the rod such that the angles were variable, friction between the rod and the ground would tend to push the skag toward the rear of the ski and cause the rod to pivot with respect to the stud. The rod would drop to a lower level due to the arc created by the straightening stud, and the nut would be angled and pushed into surface, damaging the surface. The straightening or tilting of the stud within the angled hole would also cause the hole to become distorted and damaged. By having an immovable connection between the stud and the rod, the forces applied to the angled hole by the stud are broken into one force in the x direction, perpendicular to the surface of the hole, and another force in y direction parallel to the surface of the hole. Because the forces in the x direction act on the entire surface of the cylindrical hole drilled in the ski, it is very solid and any forces directed in the y direction will cause the rod to be pulled into further contact with the bottom portion of the ski. It should be understood that the force in the y direction did not exist in a conventional construction due to the lack of the angle between the studs and the rod. It should also be understood that because the force is broken up into x and y components, the shear force, i.e. the force in the x direction, to be overcome by the weld and the stud, is also reduced. Because the studs are fixed to the rod, the nuts remain at a constant angle with the surface and thus the surface and the angled holes are not damaged.
[0020] The angle between the stud and the rod opening away from the front of the rod (towards the rear of the rod) should be measured between the stud axis and the longitudinal axis of the portion of the rod rearward of the stud. Where the portion of the rod extending rearward from the contact point of a stud with the rod is curved (as opposed to straight), and the rod has no longitudinal axis at that point, the angle between the stud and the rod should be measured between the intersection of a projection of the stud axis and the tangent to the curve of the rod through (or as close as possible to) the centre of the rod (i.e. the point that would have been along the longitudinal axis if the rod had had a longitudinal axis).
[0021] The angle between the projection of the stud axis and the ground should be measured by extending the stud axis linearly until it reaches the (horizontal level) ground and then measuring the angle at the point of intersection. For this purpose, it will be necessary to know the correct orientation of the skag with respect to the ground when the skag is correctly installed on its complimentary ski and the ski is correctly installed in its intended snowmobile. This can either be determined by physical measurement or by computer-aided design.
[0022] As used herein, the terms “first” and “second” are used merely to distinguish to like elements from one another. These terms are not intended to convey any relative positioning, quality or characteristic between or among these elements (i.e. importance, size, shape). Thus, for example, in embodiments where there are two studs present, the “first” stud can be either the front stud or the rear stud (as defined consistently with the forward direction of travel); the “second” stud will simply be the other stud (i.e. the one that is not the first stud.)
[0023] Skags of the present invention are not limited to only two studs; they may have more. It such situations it is preferred that all of the studs of the skag are angled is described hereinabove; and preferably all with the same angle. Neither of these conditions is, however, necessary, and the present invention encompasses skags wherein the additional studs (i.e. the third stud, the forth stud, etc.) are not angled, or are angled but have different angles than each other and/or than the first stud and/or the second stud.
[0024] With respect to each of the aspects of the invention, preferably both the first angle and the second angle are between 45° and 75° inclusive (they need not be they same, although it is preferred that they are); and most preferably they are 65°.
[0025] Again with respect to each aspect of the present invention, preferably the first stud and the second stud are affixed to the rod of material by welding; and more preferably each of the studs is chamfered where welded to the rod of material such that a contact between each stud and the rod of material forms an ellipse when viewed from above. It is possible however, although less preferred, that the first stud, the second stud and the rod of material be integrally formed. (The manufacture of the studs and the rod themselves is possible by any number of suitable means well known to those skilled in the art, and will therefore not be described herein.)
[0026] The studs of the present invention extend away from the rod spaced-apart from one another (i.e. there is a measurable distance between them). The rod of material of the skag has a front end, a rear end and a, preferably flat, middle therebetween. It is preferred that the studs extend away from the rod each starting a point in the middle of the rod, i.e. such that there is a length of material between the end of the rod and the start of the stud. Although less preferred, it is within the scope of the present invention for one or two of the studs to extend away from the rod of material at the end or ends of the rod.
[0027] It is preferred that it be an exterior surface of each of the studs that is threaded and adapted to receive a complimentary threaded nut. It is possible however, although less preferred, that each of the studs has a bore having an interior surface, and it is the interior surface of each bore that is threaded and adapted to receive a complimentary threaded bolt. In the present context “bore” simply refers to a cavity however created, it should not be interpreted as requiring that cavity to have actually been bored as part of its creation. It should also be understood that the studs on a skag need not have the same type of threading. Differing types of threading between or among the studs, although less preferred, is still possible. Identical threading on all of the studs is most preferred, thereby rendering their compliment (e.g. a nut or a bolt depending on the threading type) usable with all of the studs.
[0028] In another aspect of the present invention there is provided a snowmobile ski, comprising: an elongated base having a topside and an underside; a keel extending away from the underside of the base; and a skag as described hereinabove on the underside of the base at the keel, with the studs of the skag extending through holes in the ski to the topside thereof, the skag being secured to the ski via a first nut in threaded engagement with the first stud and a second nut in threaded engagement with the second stud. There is also provided a snowmobile, comprising: a frame; an engine disposed on the frame; a drive track disposed below and supported by the flame and operatively connected to the engine for propulsion of the snowmobile; a seat disposed on the frame; handlebars disposed on the frame in front of the seat; at least one ski as recited hereinabove, disposed on the frame and operatively connected to the handlebars for steering the snowmobile.
[0029] In another aspect, an embodiment of the present invention provides a skag for use on an underside of a complimentary ski for a snowmobile, the skag comprising: a rod of material having a front and rear defined consistently with a forward direction of travel of the skag when the skag is secured to the ski and the ski is connected to the snowmobile; a first stud having a first stud axis, the first stud extending away from the rod of material such that when the skag is secured to the ski and the ski is connected to the snowmobile and the snowmobile is steered straight on horizontal level ground a first angle opening away from the front of the rod of material formed between a projection of the first stud axis and the ground is less than 90°; and a second stud having a second stud axis, second stud extending away from the rod of material such that when the skag is secured to the ski and the ski is connected to the snowmobile and the snowmobile is steered straight on horizontal level ground a second angle opening away from the front of the rod of material formed between a projection of the second stud axis and the ground is less than 90°, the second stud being spaced-apart from the first stud.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Having thus generally described the nature of the present invention, reference will now be made to the accompanying drawings by way of illustration showing a preferred embodiment, in which:
[0031] FIG. 1 is a left-side elevation view of a conventional prior art skag.
[0032] FIG. 2 is a top plan view of the conventional skag of FIG. 1 ;
[0033] FIG. 3 is a left-side elevation view of a snowmobile incorporating a skag of the present invention;
[0034] FIG. 4 is a left-side elevation view of a first embodiment of a skag of the present invention;
[0035] FIG. 5 is a top plan view of the skag of the present invention;
[0036] FIG. 6 is a left-side elevation view of a snowmobile ski equipped with the skag of the present invention;
[0037] FIG. 7 is a partial cross section taken along the longitudinal axis of the skag, of a snowmobile ski equipped with the skag of the present invention;
[0038] FIG. 8 is a top plan view of a snowmobile ski equipped with the skag of the present invention;
[0039] FIG. 9 is a bottom plan view of the snowmobile ski equipped with the skag of the present invention;
[0040] FIG. 10 is a cross section taken perpendicular to the longitudinal axis of the skag, of a snowmobile ski equipped with the skag of the present invention;
[0041] FIG. 11 is a left-side elevation view of a second embodiment of a skag of the present invention;
[0042] FIG. 12 is a top plan view of the skag of FIG. 11 ;
[0043] FIG. 13 is a left-side elevation view of a third embodiment of a skag of the present invention;
[0044] FIG. 14 is a second left-side elevation view of a first embodiment of a skag of the present invention; and
[0045] FIG. 15 is a left-side elevation view of a fourth embodiment of a skag of the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0046] Referring now to FIG. 3 , a snowmobile incorporating an embodiment of the present invention is designated generally by reference numeral 110 . Although certain aspects of the present invention are applicable in other types of vehicles, the present invention has particular utility in connection with snowmobiles.
[0047] The snowmobile 110 includes a forward portion 112 and a rearward portion 114 which are defined consistently with a forward travel direction of the vehicle. The snowmobile 110 includes a frame (also known as a chassis) 116 which normally includes a rear tunnel 118 , an engine cradle 120 and a front suspension attachment assembly 122 . An engine 124 , which is schematically illustrated in FIG. 3 , is carried by the engine cradle portion 120 of the frame 116 . A ski and steering assembly (not indicated) is provided, in which two skis (of which only one is shown) 126 are positioned at the forward portion 112 of the snowmobile 110 and are attached to the front suspension attachment assembly portion 122 of the frame 116 through a front suspension assembly 128 . Each front suspension assembly 128 includes a ski leg 130 , supporting arms 132 and ball joints (not shown) for operatively joining its ski legs 130 , supporting arms 132 and a steering column 134 . The steering column 134 at its upper portion is attached to a steering device such as a handlebar 136 which is positioned forward of a rider to rotate the ski legs 130 and thus the skis 126 (on each side of the vehicle), in order to steer the vehicle.
[0048] An endless drive track 138 is positioned at the rear portion 114 of the snowmobile 110 and is disposed under tunnel 118 , being connected operatively to the engine 124 through a belt transmission system 140 that is schematically illustrated by broken lines in FIG. 3 . Thus, the endless drive track 138 is driven to run about a rear suspension assembly 142 for propulsion of the snowmobile 110 . The rear suspension assembly 142 includes a pair of slide rails 144 in sliding contact with the endless drive track 138 . The rear suspension assembly 142 also includes one or more shock absorbers 146 which may further include a coil spring (not shown) surrounding the individual shock absorbers 146 . Front and rear suspension arms 148 and 150 are provided to attach the slide rails 144 to the frame 116 . One or more idler wheels 152 are also provided in the rear suspension assembly 142 .
[0049] At the front portion 112 of the snowmobile 110 , fairings 154 enclose the engine 124 and the belt transmission system 140 , thereby providing an external shell that not only protects the engine 124 and the belt transmission system 140 , but can also be decorated to make the snowmobile 110 more aesthetically pleasing. Typically, the fairings 154 include a hood (not indicated) and one or more side panels which can be opened to allow access to the engine 124 and the belt transmission system 140 when this is required, for example, for inspection or maintenance of the engine 124 and/or the belt transmission system 140 . In the particular snowmobile 110 shown in FIG. 3 , the side panels can be opened along a vertical axis to swing away from the snowmobile 110 . A windshield 156 may be connected to the fairings 154 near the front portion 112 of the snowmobile 110 or directly to the handlebar 136 . The windshield 156 acts as a wind screen to lessen the force of the air on the rider while the snowmobile 110 is moving.
[0050] The engine 124 is an of internal combustion engine that is supported on the frame 116 and is located at the engine cradle portion 120 . The internal construction of the engine 124 may be of any known type, however the engine 124 drives an engine output shaft 129 that rotates about a horizontally/laterally disposed axis that extends generally transversely to a longitudinal centerline 161 extending in a front to rear direction of the snowmobile 110 . The engine output shaft 129 drives the belt transmission system 140 for transmitting torque to the endless drive track 138 for propulsion of the snowmobile 110 .
[0051] A straddle seat 158 is positioned atop the frame 116 and extends from the rear portion 114 of the snowmobile 110 to the fairings 154 . A rear portion of the seat 158 may include a storage compartment or can be used to accommodate a passenger seat (not indicated). Two footrests (one shown) 160 are positioned on opposite sides of the snowmobile 110 below the seat 158 to accommodate the driver's feet.
[0052] Snowmobile 110 has skis 126 having skags of the present invention. FIGS. 4 and 5 show the skag 162 . Skag 162 has a rod 163 having a longitudinal axis 164 which is parallel to the forward direction of travel of the skag 162 when the skag 162 is properly installed on a complimentary ski (not shown in those figures), indicated by the arrow 166 , of the skag 162 . The front 168 and the rear 170 of the rod 163 are typically bent upward so that the ends 169 , 171 do not hook into the ground when the skag 162 is in use. A flat middle 169 of the skag 162 , from which the studs 174 , 176 extend, is between the front 168 and the rear 170 . The rod 163 is made steel, and has a square cross-section.
[0053] Carbides 172 are fixed to the bottom of the rod 163 to further enhance the steering capabilities of the skag 162 . (Although it is preferable to place carbides on the bottom of the rod, by no means is the present invention limited to a skag having carbides.)
[0054] A front stud 174 and a rear stud 176 extend upwardly from the rod 163 at angles θ and γ respectively which open away from the front 168 of the skag 162 and are each 65°. The studs 174 and 176 are circular in cross-section; the exterior surfaces thereof are threaded with threads 178 and receive a nut 190 . Each of the studs 174 , 176 has a stud axis 180 . (In the description of this embodiment the studs themselves have been gave different reference numbers (to separately identify them) but their various portions and features of have not (simply for ease of reference). This was not intended to limit the invention.)
[0055] Each stud 174 , 176 has a free portion 182 and a contact portion 184 . The free portion 182 is adapted to receive a nut 190 (or other threaded fastening device) (shown in later figures to co-operate with the stud 174 , 176 and fasten the skag 162 to a snowmobile ski. The contact portion 184 is fixed to the rod 163 by welding. The contact portion 184 is chamfered at an angle similar to angles 0 and y for the front stud 174 or rear stud 176 respectively to create an elliptical contact perimeter 186 between the respective stud 174 , 176 and the rod 163 .
[0056] FIGS. 6 and 7 show a side view of a ski 126 equipped with the skag 162 of the present invention. The skag 162 is placed on a bottom surface 194 of a keel 192 of the ski 126 such that studs 174 , 176 protrude through holes 188 in the keel 192 , best seen in FIG. 7 . Nuts 190 are threaded to the front and rear studs 174 , 176 to sandwich the ski 126 between the skag 162 ; the nuts 190 thus secure the skag 162 to the ski 126 .
[0057] As would be recognized by a person skilled in the art, the forces applied to the ski 126 by the ski leg 130 during forward movement of the snowmobile and the forces applied to the skag 162 from the contact with the ground 50 are always in the opposite direction due to the friction between the skag 162 and the ground 50 that it contacts. In the forward operation of the snowmobile, the skag 162 is constantly being “pushed” towards the rear of the ski 126 , and thus the studs 174 , 176 and the welds between the studs 174 , 176 and the rod 163 must resist bending and shear in securing the skag 162 to the ski 126 . Having the studs 174 , 176 angled and fixed with the rod offers several advantages of dealing with these stresses created as described hereinabove.
[0058] As can also be seen in FIG. 7 , the nut contact surface 196 of ski 126 is angled with respect to the longitudinal axis 164 by angles β and δ for the front stud 174 and the rear stud 176 respectively, which, in this case, is equal to 90°−θ and 90°−γ respectively. It would be appreciated that in order to have the nut 190 , or the head of a bolt (not shown), evenly contact surface 196 , it is desirable to have such a relationship between θ and β and between γ and δ.
[0059] In this embodiment, having the studs 174 , 176 angled rearwardly with respect to the rod 163 , also provides more access to the nuts 190 behind a ski leg 130 . Because the ski leg 130 is constructed to be angled toward the rear, having the studs angled rearward provides better access to the rear nuts with certain tools than if the studs were not angled. The angled studs also prevent a user from installing the skags on the bottom of a ski in the reverse orientation as, the studs would not pass through the angled holes in the bottom of the ski.
[0060] FIGS. 8, 9 and 10 show top and bottom plan views and a cross-sectional view respectively of a ski 526 equipped with two skags 562 , 602 of the present invention. (Skis may have single or multiple skags.) Ski 526 has skag 562 attached at a first side 598 of the ski 526 and a second skag 602 attached between the first side 598 and a second side 600 , down the center, of the ski 526 . Best seen in FIG. 10 , the second side 600 of the ski 526 includes a lip 604 extending downward therefrom. A handle 606 is attached at the front portion 608 of the ski 526 to provide a grip for lifting ski 526 when needed. Also seen in FIG. 10 , skags 562 and 602 include carbides 610 fixed to the bottom thereof to further enhance the turning capabilities of the ski as described above.
[0061] FIGS. 11 and 12 show a second embodiment of the present invention. Skag 262 includes a rod 263 having two angled ends 268 , 270 . The two ends 268 , 270 are threaded with threads 278 to form studs 274 and 276 . As with studs 174 , 176 , the ends 268 , 270 forming the studs 274 and 276 are angled in a direction opposite to that of the forward travel direction 266 of the skag 262 . The studs 274 , 276 define a thread axis 280 which is angled with the longitudinal axis 264 of the skag 262 at the preferred angles θ and γ for studs 274 and 276 respectively. Although similar to skag 162 , skag 262 no longer requires that the studs be welded to the rod but rather the ends 270 , 268 of the rod have been simply bent and threaded to form the studs 274 , 276 . Direct molding in this shape would have also possible. The skag 262 benefits from some of the same advantages discussed above with respect to skag 162 due to its rearward angled studs 274 , 276 .
[0062] FIG. 13 shows a third embodiment of the present invention. Skag 362 includes a rod 363 having two angled ends 368 , 370 forming studs 374 , 376 . Studs 374 , 376 each have a threaded bore 379 therein to receive a complimentary threaded nut 391 . Each stud 374 , 376 has a stud axis 380 which is co-axial with a longitudinal axis of the bore 391 . (An embodiment where they are not co-axial is also possible.) The bores 391 are physically bored into the studs 374 , 376 , however they could be otherwise formed by any number of methods known to persons skilled in the art.
[0063] FIG. 14 shows a skag of the embodiment of FIG. 4 wherein the angle α between projection 181 of the stud axis 180 of stud 174 and the ground 50 , and the angle ω between the projection 181 of the stud axis 180 of stud 176 , are shown. Both angles are 65°.
[0064] FIG. 15 shows a fourth embodiment of the present invention. Skag 462 has a curved rod 463 having no longitudinal axis. The front 468 and the rear 470 of the rod 463 are curved upward. A curved middle 469 of the skag 462 , from which the studs 474 , 476 extend, is between the front 468 and the rear 470 . The rod 463 is made steel, and has a square cross-section. As skag 462 has no longitudinal axis, the angles π and ρ are measured between the projection 481 of the stud axis 480 and the tangent 483 to the curve of the rod through (or as close as possible to) the centre of the rod.
[0065] Modifications and improvements to the above-described embodiments of the present invention may become apparent to those skilled in the art. The foregoing description is intended to be exemplary rather than limiting. The scope of the present invention is therefore intended to be limited solely by the scope of the appended claims.
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A skag having a rod/elongated rod and rearwardly-angled threaded studs upwardly-extending immovably from the rod. The skag adapted to be connected to the bottom of a snowmobile ski to enhance the steering capabilities the snowmobile ski. The studs being angled with respect to a longitudinal axis of the skag in a direction opposite to that of the forward travel direction of the skag to decrease the shear stress on the weld fixing the stud to the rod and providing a security against installing the skags in the wrong orientation on the bottom of the ski.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to 4-chloro-3,5-diaminophenyl acetates, preparations thereof and curing agents for polyurethane elastomer using the same compound.
2. Description of the Prior Art
It has been well known that aromatic diamines are used as curing agents for polyurethane elastomer. Various aromatic diamines have been proposed. However, various characteristics have been required for curing agents used for polyurethane elastomer and satisfactory aromatic diamines could not be obtained. The characteristics required for curing agent include
(1) low melting solid or liquid from the viewpoint of processability and labour hygiene and saving of energy;
(2) suitable pot-life as a time from mixing the curing agent with a mixture of polyisocyanate and polyol or a prepolymer having terminal isocyanato group to lose fluidity in a casting, from the viewpoint of processability;
(3) suitable set time as a demoldable time from pouring the mixture to taking out the casted product from the viewpoint of processability especially efficiency;
(4) easy synthesis and stability of the object curing agent; and
(5) formation of a cured polyurethane elastomer having excellent mechanical characteristics.
These characteristics are inconsistant each other, for example, a trouble of processing is caused by a short pot-life when a short set time is expected. It has been difficult to obtain a curing agent having suitable balance for satisfying these required characteristics.
For example, 3,3'-dichloro-4,4'-diaminodiphenyl methane is a curing agent for polyurethane elastomer having excellent mechanical characteristics, however, it has high melting point (100° to 106° C.) whereby the processability is disadvantageously inferior.
It has been known that 4-chloro-3,5-diaminobenzoates are curing agents for polyurethane elastomer having excellent mechanical characteristics which has long pot-life but the set time disadvantageously is long and a melting point is mostly high. (Japanese Patent Publication No. 51959/1972).
The inventors have studied to obtain a curing agent which has the satisfactory characteristics required for the curing agent for polyurethane elastomer and have synthesized many compounds.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel compounds which are useful as a curing agent for polyurethane elastomer and an intermediate for pharmaceutical and agrochemical compound.
It is another object of the present invention to provide a curing agent for polyurethane elastomer which has low melting point, long pot-life, short set time, stable and which is easily synthesized and which gives a cured polyurethane elastomer having excellent mechanical characteristics.
The novel compounds of the present invention are 4-chloro-3,5-diaminophenyl acetates having the formula ##STR2## wherein R represents an alkyl group.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The novel compounds of 4-chloro-3,5-diaminophenyl acetates include the following compounds:
Compound (1): methyl 4-chloro-3,5-diaminophenyl acetate;
Compound (2): ethyl 4-chloro-3,5-diaminophenyl acetate;
Compound (3): n-propyl 4-chloro-3,5-diaminophenyl acetate;
Compound (4): i-propyl 4-chloro-3,5-diaminophenyl acetate;
Compound (5): n-butyl 4-chloro-3,5-diaminophenyl acetate;
Compound (6): i-butyl 4-chloro-3,5-diamonophenyl acetate;
Compound (7): sec-butyl 4-chloro-3,5-diaminophenyl acetate;
Compound (8): n-octyl 4-chloro-3,5-diaminophenyl acetate.
These compounds have satisfactory characteristics as a curing agent for polyurethane elastomer.
The novel compounds of 4-chloro-3,5-diamonophenyl acetates can be obtained by simultaneously nitrating and hydrolyzing 4-chlorobenzylcyanide and esterifying the resulting 4-chloro-3,5-dinitrophenyl acetate and reducing the resulting 4-chloro-3,5-dinitrophenyl acetate. The reactions are shown as follows. ##STR3##
In the nitration and hydrolysis of 4-chlorobenzylcyanide, 4-chloro-benzylcyanide is mixed with 5 to 20 molar times, preferably 7 to 15 molar times of 95 to 98% sulfuric acid at lower than 30° C. and 2.5 to 4 molar times of 60 to 99% nitric acid is added at 20° to 40° C. and a reaction is performed at 20° to 40° C. for 0.5 to 2 hours and at 50° to 70° C. for 5 to 9 hours. After the reaction, the resulting reaction mixture is poured into water and the precipitated crystals are filtered to obtain 4-chloro-3,5-dinitrophenyl acetic acid in high yield.
The esterification of 4-chloro-3,5-dinitrophenyl acetic acid is performed by reacting with an aliphatic alcohol in the presence of an acid catalyst or in the presence of an acid catalyst and an azeotropic solvent.
Suitable acid catalysts are inorganic or organic acids used in esterification of an acid and an alcohol such as hydrochloric acid, sulfuric acid and p-toluenesulfonic acid, etc.
Suitable azeotropic solvents are solvents to form azeotropic mixtures with the aliphatic alcohol used in the reaction and water formed by the reaction, such as carbon tetrachloride, benzene, toluene, xylene and cyclohexane.
The reaction temperature is usually in a range of 50° to 150° C. preferably a refluxing temperature of the reaction mixture and the reaction time is in a range of 2 to 15 hours.
In the esterification of 4-chloro-3,5-dinitrophenyl acetic acid, 4-chloro-3,5-dinitrophenyl acetic acid is reacted with a chlorinating agent such as phosphorus pentachloride and thionyl chloride and the resulting 4-chloro-3,5-dinitrophenyl acetic chloride is reacted with an aliphatic alcohol in the presence of dehydrogen chloride agent in the absence of a solvent or in an inert solvent.
Suitable inert solvents include carbon tetrachloride, benzene, toluene and xylene.
Suitable dehydrogen chloride agents include organic tertiary amines and inorganic bases such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide and sodium carbonate.
The reaction temperature is in a range of 0° to 150° C. and the reaction time is in a range of 1 to 6 hours.
Suitable aliphatic alcohols used in the esterification of 4-chloro-3,5-dinitrophenyl acetic acid include methanol, ethanol, n- or i-propanol, n-, i- or sec-butanol, n- or i-amyl alcohol, n-hexyl alcohol and n-octyl alcohol.
After the esterification, the resulting reaction mixture is treated by a conventional purification to obtain 4-chloro-3,5-dinitrophenyl acetate in high yield.
In the reduction of 4-chloro-3,5-dinitrophenyl acetate, various reduction such as reduction with iron in the presence of a catalytic amount of an acid, such as hydrochloric acid, sulfuric acid or acetic acid; reduction with tin or tin chloride and conc. hydrochloric acid; and reduction with hydrogen in the presence of a catalyst such as Pt, Ni or Pd.
For example, in the reduction with iron in the presence of a catalytic amount of an acid, a solution of 4-chloro-3,5-dinitrophenyl acetate in a solvent such as benzene, toluene and xylene is added to a mixture of iron powder, an acid, water and a solvent such as benzene, toluene and xylene and the reaction is performed by refluxing for 1 to 10 hours. After the reaction, the reaction mixture is treated by a conventional purification to obtain 4-chloro-3,5-diaminophenyl acetates in high yield.
In the process for producing polyurethane elastomer using the curing agent of the novel compound of 4-chloro-3,5-diaminophenyl acetate of the present invention, the curing agent is heat-melted and admixed with a heated reaction mixture of a polyisocyanate and a polyol or a prepolymer having terminal isocyanato group or a polyisocyanate is admixed with a mixture of a polyol and the curing agent. The mixture is thoroughly mixed and poured into a mold to cure it.
Suitable polyisocyanates include hexamethylenediisocyanate (HMDI), cyclohexanediisocyanate, 2,4-tolylenediisocyanate (2,4-TDI), 2,6-tolylenediisocyanate (2,6-TDI) and mixture of 2,4-tolylenediisocyanate and 2,6-tolylenediisocyanate, dimer and trimer of 2,4-tolylenediisocyanate, xylylenediisocyanate (XDI), meta-xylylenediisocyanate (MXDI), m-phenylenediisocyanate, 4,4'-biphenyldiisocyanate, diphenylehter-4,4'-diisocyanate, 3,3'-ditoluene-4,4'-diisocyanate (TODI), dianisidinediisocyanate (DADI), 4,4'-diphenylmethanediisocyanate (MDI), 3,3'-dimethyl-4,4'-diphenylmethanediisocyanate, 1,5-naphthalenediisocyanate (NDI) and triphenylmethanetriisocyanate (TTI) and desired polyisocyanate used in preparations of polyurethane elastomers can be used.
Suitable polyols include polyols having a molecular weight of 500 to 8,000 and two or more hydroxyl groups such as aliphatic polyester glycols obtained by condensing an aliphatic glycol and a dicarboxylic acid and chain-extending it such as polyethyleneadipate, polybutyleneadipate and polypropyleneadipate; polyalkyleneether glycols obtained by a ring-opening polymerization of ethyleneoxide, propyleneoxide or tetrahydrofuran such as polypropyleneetherglycol and tetramethyleneether glycol; polyesterglycols obtained by a ring-opening polymerization of ε-caprolactone; terminal hydroxylated polybutadiene; alkyleneoxide copolymers; copolyesters of glycol and a dicarboxylic acid; polyesterpolyols as copolyesters of long chain diols of mixture of aromatic glycols or a mixture of polyol e.g. glycerin and trimethylolpropane and an aliphatic glycol and a dicarboxylic acid; and polyetherpolyols obtained by a ring-opening polymerization of ethyleneoxide, propyleneoxide or tetrahydrofuran with an initiator of a polyol such as glycerin and trimethylolpropane.
Suitable urethaneprepolymers having terminal isocyanates are obtained by reacting said polyol with excess of said polyisocyante such as prepolymers having terminal isocyanate group derived from a polyether or a polyesterglycol; such as prepolymers obtained by reacting polytetramethyleneglycol with excess of tolylenediisocyanate; prepolymers obtained by reacting polyethyleneadipate with excess of tolylenediisocyanate, prepolymers obtained by reacting polycaprolactonediol with excess of tolylenediisocyanate.
A ratio of the curing agent of 4-chloro-3,5-diaminophenyl acetate of the present invention is depending upon a polyol, a polyisocyanate or a prepolymer having terminal isocyanate group and it is usually in a range of about 0.8 to 1.2 preferably 0.80 to 1.0 equivalent of amino group of the curing agent or a total of amino group of the curing agent and hydroxyl group of the polyol per 1 equivalent of the isocyanate group.
A ratio of hydroxyl group of the polyol to the amino group of the curing agent can be varied in broad range and preferably in a range of 0.5 to 5 equivalent of hydroxyl group per 1 equivalent of the amino group.
The curing agents of the present invention are solids having a low melting point whereby the processability is highly improved in comparison with the use of the conventional curing agent and polyurethane elastomers having excellent mechanical characteristics can be advantageously obtained.
The present invention will be further illustrated by certain examples and references which are provided for purposes of illustration only and are not intended to be limiting the present invention.
EXAMPLE 1
Preparation of Compound No. 1
In a 1 liter flask equipped with a thermometer, a condenser, a dropping funnel and a stirrer, 250 ml of 97% sulfuric acid (4.55 mole) was charged and 75.8 g (0.5 mole) of 4-chlorobenzylcyanide was added dropwise and a mixed acid of 77 ml of 99% nitric acid (1.84 mole) and 200 ml of 97% sulfuric acid (3.64 mole) was added dropwise during 2 hours.
After the addition, the reaction was performed at 30° C. for 1 hour and then, at 60° C. for 7 hours. After the reaction, the resulting reaction mixture was poured into 2 liters of ice water and a precipitated crystal was separated by a filtration and washed with water and dried to obtain 124.0 g of pale yellow powdery crystals having a melting point of 167.5° to 172.0° C. of 4-chloro-3,5-dinitrophenyl acetic acid (95.2% of yield based on 4-chlorobenzylcyanide).
In a 500 ml flask, 192.0 g (6.0 mole) of methanol, 5 g of conc. sulfuric acid (0.05 mole) and 78.2 g (0.3 mole) of 4-chloro-3,5-dinitrophenyl acetic acid were charged and they were refluxed for 6 hours to react them. After the reaction, the reaction mixture was poured into 2 liters of water and the precipitated crystal was separated by a filtration and washed with water and dried to obtain 75.0 g of pale yellow needle-like crystal having a melting point of 80.0° to 81.5° C. of 4-chloro-3,5-dinitrophenyl acetic acid (91.0% of yield based on 4-chloro-3,5-dinitrophenyl acetic acid).
In a 1 liter flask, 174 g (3.12 mole) of iron powder, 3.0 g (0.05 mole) of acetic acid, 170 g (9.4 mole) of water and 300 ml of toluene were charged, and a solution of 68.6 g (0.25 mole) of methyl 4-chloro-3,5-dinitrophenyl acetate in 100 ml of toluene was added dropwise during about 1 hour to the mixture under refluxing with stirring, and the mixture was refluxed for 3 hours to react them. After the reaction, sodium bicarbonate was added to neutralize acetic acid and the resulting reaction mixture was filtered in hot to separate iron sludge and then, water phase was separated from the resulting filtrate and toluene was distilled off from the organic phase to obtain crystal and the crystal was recrystallized from a mixed solvent of toluene-n-hexane to obtain 44.0 g of methyl 4-chloro-3,5-diaminophenyl acetate Compound No. 1 (82.0% of yield based on methyl 4-chloro-3,5-dinitrophenyl acetate). ##STR4##
Appearance: Pale yellow needle-like crystal.
Yield: 71.0% (based on 4-chlorobenzyl cyanide: starting material).
Melting point: 59.5° to 61.0° C.
Characteristic IR spectrum:
NH 2 : 3,430 cm -1 , 3,350 cm -1 ,
C═O: 1,720 cm -1 .
The compound was also identified by NMR.
EXAMPLE 2
Preparation of Compound No. 2
In accordance with the process of Example 1 except using ethanol and ethyl 4-chloro-3,5-dinitrophenyl acetate instead of methanol and methyl 4-chloro-3,5-dinitrophenyl acetate, the reaction was carried out to obtain ethyl 4-chloro-3,5-diaminophenyl acetate. The results are shown in Table 1.
EXAMPLES 3 to 7
In accordance with the process of Example 1 except using various aliphatic alcohol, 150 ml of toluene instead of methanol; and using various 4-chloro-3,5-dinitrophenyl acetate instead of methyl 4-chloro-3,5-dinitrophenyl acetate, the reactions were carried out to obtain various 4-chloro-3,5-diaminophenyl acetates. The results are shown in Table 1.
TABLE 1______________________________________ ##STR5## ##STR6## ##STR7##______________________________________ Intermediate ProductAlcohol (IV) (V)Ex. (III) R R______________________________________2 C.sub.2 H.sub.5 OH C.sub.2 H.sub.5 Compound No. 2 C.sub.2 H.sub.53 n-C.sub.3 H.sub.7 OHn-C.sub.3 H.sub.7Compound No. 3n-C.sub.3 H.sub.74 i-C.sub.3 H.sub.7 OHi-C.sub.3 H.sub.7Compound No. 4i-C.sub.3 H.sub.75 n-C.sub.4 H.sub.9 OHn-C.sub.4 H.sub.9Compound No. 5n-C.sub.4 H.sub.96 i-C.sub.4 H.sub.9 OHi-C.sub.4 H.sub.9Compound No. 6i-C.sub.4 H.sub.97 sec-C.sub.4 H.sub.9 OHsec-C.sub.4 H.sub.9Compound No. 7sec-C.sub.4 H.sub.9______________________________________ AppearanceYield physical CharacteristicEx. (%) property IR spectrum______________________________________2 76.3 yellowish brown NH.sub.2 : 3430cm.sup.-1 ; prism 3350cm.sup.-1 m.p.67.0-68.5° C. CO: 1720cm.sup.-13 70.5 pale yellow NH.sub.2 : 3430cm.sup.-1 ; needle-like 3350cm.sup.-1 m.p.43.0-43.5° C. CO: 1720cm.sup.-14 76.9 yellowish brown NH.sub.2 : 3430cm.sup.-1 ; bulk 3350cm.sup.-1 m.p.77.5-80.0° C. CO: 1720cm.sup.-15 80.0 yellowish brown NH.sub.2 : 3430cm.sup.-1 ; bulk 3350cm.sup.-1 m.p.39.0-40.0° C. CO: 1720cm.sup.-16 77.4 yellowish brown NH.sub.2 : 3430cm.sup.-1 ; bulk 3350cm.sup.-1 m.p.41.5-43.0° C. CO: 1720cm.sup.-17 72.7 yellowish brown NH.sub.2 : 3430cm.sup.-1 ; bulk 3350cm.sup.-1 m.p.83.0-85.5° C. CO: 1720cm.sup.-1______________________________________
EXAMPLE 8
The compound No. 1 of methyl 4-chloro-3,5-diaminophenyl acetate was used as a curing agent. 10.2 Gram of the compound No. 1 was melted and mixed with 100 g of a prepolymer obtained from polytetramethyleneglycol and tolylenediisocyanate (Adiplene L-100 manufactured by Du Pont) (4.19 wt.% of isocyanato group) at 90° C. with stirring for about 60 seconds. The mixture was poured into a mold having a size of 100 mm×250 mm×2 mm heated at 100° C. and it was cured at 100° C. for 1 hour and it was demolded and then, heated at 100° C. for 15 hours to perform an after-curing. The resulting polyurethane elastomer was aged at 25° C. in a relative humidity of 50% for 7 days and characteristics of the polyurethane elastomer were measured by Japanese Industrial Standard K 6301. The results are shown in Table 2.
EXAMPLES 9 to 14
In accordance with the process of Example 8 except using various 4-chloro-3,5-diaminophenyl acetates as the curing agent, polyurethane elastomers were prepared and characteristics of polyurethane elastomers were measured. The results are shown in Table 2.
EXAMPLE 15
7.3 Gram of methyl 4-chloro-3,5-diaminophenyl acetate as a curing agent was melted and mixed with 100 g of a prepolymer obtained from polyethyleneadipate and tolylenediisocyanate (Cyaprene A 8 manufactured by ACC) (3.0 wt.% of isocyanato groups) at 90° C. with stirring for about 60 seconds. The mixture was poured into a mold having a size of 100 mm×250 mm×2 mm heated at 100° C. and it was cured at 100° C. for 1 hour and it was demolded and then, heated at 100° C. for 15 hours to perform an after-curing. The resulting polyurethane elastomer was aged at 25° C. in a relative humidity of 50% for 7 days and characteristics of the polyurethane elastomer were measured by Japanese Industrial Standard K 6301. The results are shown in Table 2.
EXAMPLES 16 to 21
In accordance with the process of Example 15 except using various 4-chloro-3,5-diaminophenyl acetates as the curing agent, polyurethane elastomers were prepared and characteristics of polyurethane elastomers were measured. The results are shown in Table 2.
TABLE 2______________________________________Example 8 9 10 11 12 13 14______________________________________Curing agentCompound No. No.1 No.2 No.3 No.4 No.5 No.6 No.7Amount of curingagent (g) 10.2 10.8 11.5 11.5 12.2 12.2 12.2Equivalent ratio ofNH.sub.2 /NCO 0.95 0.95 0.95 0.95 0.95 0.95 0.95Pot-life (min.) 11 11 12 12 11 12 12Set time (min.) 30 30 30 30 30 30 30Physical PropertiesHardness(Shore-A) 95 94 94 94 94 94 94100% modulus(Kg/cm.sup.2) 101 98 97 103 105 96 107300% modulus(Kg/cm.sup.2) 147 134 147 168 135 128 144Tensile strength(Kg/cm.sup.2) 342 336 319 371 302 305 354Elongation (%) 480 500 460 460 470 500 460Tear strength(Kg/cm) 101 98 92 105 91 98 93Rebound elasticity(%) 59 59 58 60 59 57 59Compressionpermanent set (%) 32 34 30 35 37 37 32Example 15 16 17 18 19 20 21______________________________________Curing agentCompound No. No.1 No.2 No.3 No.4 No.5 No.6 No.7Amount of curingagent (g) 7.3 7.8 8.2 8.2 8.7 8.7 8.7Equivalent ratio ofNH.sub.2 /NCO 0.95 0.95 0.95 0.95 0.95 0.95 0.95Pot-life (min.) 11 11 12 12 11 12 12Set time (min.) 30 30 30 30 30 30 30Physical PropertiesHardness (Shore-A) 90 90 90 90 90 89 89100% modulus(Kg/cm.sup.2) 57 58 57 58 56 54 55300% modulus(Kg/cm.sup.2) 78 81 82 80 79 77 77Tensile strength(Kg/cm.sup.2) 578 533 540 563 495 460 479Elongation (%) 710 700 770 730 760 750 740Tear strength(Kg/cm) 97 94 99 98 92 90 93Rebound elasticity(%) 54 53 53 53 51 51 50Compressionpermanent set (%) 40 41 43 41 43 46 45______________________________________
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4-Chloro-3,5-diaminophenyl acetates having the formula ##STR1## wherein R represents an alkyl group are useful as curing agent for polyurethane elastomer and intermediates for pharmaceutical and agrochemical compounds and are produced by simultaneously nitrating hydrolyzing 4-chlorobenzylcyanide and esterifying the resulting 4-chloro-3,5-dinitrophenyl acetic acid and then reducing the resulting ester.
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FIELD OF THE INVENTION
[0001] The present invention relates to an ultrasonic treatment apparatus and a cartridge comprised of an ultrasonic coupling and a protective cover.
BACKGROUND OF THE INVENTION
[0002] Ultrasound from a focused ultrasonic transducer can be used to selectively treat regions within the interior of the body. Ultrasonic waves are transmitted as high energy mechanical vibrations. These vibrations induce tissue heating as they are damped, and they can also lead to cavitation. Both tissue heating and cavitation can be used to destroy tissue in a clinical setting. However, heating tissue with ultrasound is easier to control than cavitation. Ultrasonic treatments can be used to ablate tissue and to kill regions of cancer cells selectively. This technique has been applied to the treatment of uterine fibroids, and has reduces the need for hysterectomy procedures.
[0003] To selectively treat tissue, a focused ultrasonic transducer can be used to focus the ultra sound on a particular treatment volume. The transducer is typically mounted within a medium, such as degassed water, that is able to transmit ultrasound. Actuators are then used to adjust the position of the ultrasonic transducer and thereby adjust the tissue region that is being treated. U.S. Pat. No. 5,590,653 describes a medical treatment apparatus where the position of an ultrasonic transducer is adjustable and is integrated into a patient table.
[0004] Standard medical imaging techniques are commonly used to plan the ultrasound treatment and can also be used to guide the treatment. Magnetic Resonance Imaging (MRI), Computed Tomography y (CT), and ultrasonic imaging have been used for the planning and guiding of ultrasonic treatments. Focused ultrasonic transducers typically have a limited range over which they can be actuated, so the patient must be positioned properly relative to the ultrasonic treatment apparatus. Ultrasound is not able to be transmitted to the body through air, so an ultrasound coupling such as ultrasonic gel, an ultrasonic gel pad, or degassed water is used to transmit the ultrasound from the ultrasonic treatment apparatus to the skin of the patient. Typically a membrane such as Mylar is used to form a boundary between the ultrasonic treatment apparatus and the medium used to conduct ultrasound to the patient.
[0005] A problem with current ultrasonic treatment apparatuses is that the Mylar membranes are fragile and that the ultrasound coupling may not form a good path for the ultrasound if the patient is positioned on the coupling more than once. For many treatment procedures, the patient is positioned relative to the treatment apparatus and a medical imaging technique is used to check the orientation of the patient's anatomy relative to the ultrasonic transducer. If the patient is not orientated relative to the ultrasonic transducer properly, he or she will need to be repositioned. This can cause the ultrasound coupling to be damaged. In this case the coupling will need to be replaced, and this typically means that the process of orientating the patient relative to the ultrasonic transducer needs to be started again. Additionally when the patient is positioning himself or herself on the ultrasonic treatment apparatus, the Mylar window can be damaged, or the ultrasonic coupling disturbed.
SUMMARY OF THE INVENTION
[0006] The invention provides for an ultrasonic treatment apparatus and a cartridge as claimed in the independent claims. Embodiments of the invention are given in the dependent claims.
[0007] Embodiments of the invention address the aforementioned problems by protecting the region that transmits ultrasound to the patient with a protective cover. This protects ultrasound gel pad or other ultrasound coupling during the patient setup, positioning and possible test images. This also protects any ultrasound membrane, such as Mylar, when the patient is stepping onto or off of the table or patent support. An ultrasound membrane is defined to be a thin membrane which is adapted for the transmission of ultrasound. The cover can also be used to protect the ultrasound membrane when the ultrasonic treatment apparatus is not in use.
[0008] Embodiments of the invention provide for an ultrasonic treatment apparatus comprised of a patient support that is able to support a patient, an ultrasonic transducer that is used for the ultrasonic treatment of patients, a region which is formed in the patient support for transmitting ultrasound from the ultrasound transducer system to a treatment zone on the patient, and a protective cover for covering the region. The treatment zone is defined to be the region of the patient which is being treated by the ultrasonic treatment apparatus.
[0009] The protective cover is able to be removed from the region when the patient is positioned relative to the treatment zone such that the treatment zone is able to receive treatment from the ultrasound transistor system. This has the advantage that typically an ultrasonic coupling agent such as an ultrasonic gel or an ultrasonic gel pad is used to couple the ultrasound from the transducer system to the skin of the patient. The patient is able to position him or herself properly on the patient support when the protective cover is in place without causing the ultrasound coupling agent to be disturbed. When the patient is in the correct position, then the protective cover can be removed from the region. This is more pleasant for the patient than having to repeatedly be repositioned and replacing the ultrasonic coupling material, and it also increases the workflow and allows examinations or treatments to proceed more rapidly.
[0010] In another embodiment the patient support has a surface which slopes towards the region which transmits the ultrasound. This sloped region supports the patient and serves to partially support the patient so that when the protective cover is removed there is less weight from the patient on the protective cover. This has the advantage that it is easier to remove the protective cover and it is more comfortable for the patient. The sloped surface is also more comfortable for the patient and aids in properly positioning the patient.
[0011] In another embodiment the ultrasonic treatment apparatus indicates a medical imaging device. The advantage of incorporating the medical imaging device is that the medical imaging device can be used for guiding the ultrasonic treatment. This allows physicians to precisely locate and treat regions within the body of the patient. The medical imaging device for this type of procedure is comprised of an MRI scanner, a CT scanner or an ultrasound imaging system. The advantage of this is that these imaging techniques are all compatible with the ultrasound treatment and are able to image the tumors during the ultrasound treatment.
[0012] Guiding the ultrasonic treatment is herein defined as meaning using a medical image device before or during or after an ultrasonic treatment to properly locate and treat a volume within a patient. This can be implemented in different ways. The entire treatment apparatus can be within the volume that is able to be imaged using a medical imaging device during the guiding process. Another alternative is that ultrasonic transducer and imaging device are in separate locations. The patient can be moved with a movable patient support between the imaging apparatus and the ultrasonic transducer.
[0013] In another embodiment there is an ultrasound membrane which is adapted for transmitting ultrasound which separates the ultrasound transducer system from an ultrasound coupling. The ultrasound coupling is adapted to transmit ultrasound from the ultrasound membrane to the dermis of a patient. This has the advantage that the ultrasound membrane separates the acoustic or ultrasound coupling material from the ultrasound transducer system. Materials used for ultrasound coupling are typically liquid or gel like and the membrane protects the ultrasonic transistor system from the ultrasound coupling material.
[0014] In another embodiment the protective cover is slideably engaged. This is very advantageous, because the patient can be resting against the protective cover and the protective cover can simply be slid away. By sliding the cover away the patient does not need to be moved or be repositioned.
[0015] In another embodiment the protective cover is comprised of two slideably engaged plates. As in the previous embodiment this has the advantage that the patient can remain in place when the protective cover is removed. The two slideably removable plates are particularly advantageous for MRI and CT scanners. The patient typically lies on a bed and the plates are on either side of the body. An operator simply removes each of these two plates and the protective cover is removed.
[0016] In another embodiment the protective cover is detached from the ultrasound treatment apparatus when the protective cover is removed. This is advantageous, because many times the patient support for supporting the patient would be operable for moving the patient within the bore of an MRI scanner or CT scanner. Removing the protective plates allows the patient to be moved more easily within a diagnostic apparatus.
[0017] In another embodiment the ultrasonic apparatus can also have compartments contained within the patient support. These compartments can be used to hold the protective cover when it is removed from the region. This has the advantage that if the cover is completely contained within the patient support then a patient does not need to be removed from the magnet or from a CT scanner when the protective cover is removed. For the embodiment where the protective cover is comprised of two slideably engaged plates, the operator would typically do a preliminary scan to see if the positioning of the ultrasonic transducer relative to the treatment zone is correct. Then the patient would be removed from the diagnostic region where the operator is able to remove the slideably engaged plates. The embodiment where the compartments are contained within the patient support would allow for an apparatus where the protective cover can be removed when the patient is within a medical imaging device.
[0018] In another embodiment the compartments are aligned so that the translational motion of the protective cover is aligned with the length of the patient support. This has the advantage that along the length of the patient support, there is space where the cover can fit. This means that it would be possible to devise a mechanism or system for retracting the covers without having the patient removed from the treatment zone.
[0019] In another embodiment the ultrasonic treatment apparatus is further comprised of an actuator which is operable for removing the protective cover from the region. This is an advantage because the operator does not need to manually remove the protective cover, and it can be done automatically when the patient is within a medical scanner. The actuator is adapted for receiving a control signal that signals when the protective cover should be removed from the region and wherein the actuator is further adapted to remove the protective cover from the region upon receiving this control signal. This is an advantage, because a control or computer system can be used for controlling when the protective cover is removed. This allows the removal of the protective cover to be automated.
[0020] In another embodiment the ultrasonic treatment apparatus is operable for ablating tissue. This is advantageous because it allows tissue to be treated without invasive surgery. This reduces treatment costs and is less invasive and leads to the patient healing more rapidly.
[0021] In another embodiment the ultrasonic treatment apparatus is also operable for treating cancer tumors. This has the advantage also that it is less invasive and does not require surgery. This method also has the advantage that it does not damage the patient's immune system in the way that chemotherapy and radiation therapy can. In another aspect the invention provides for a cartridge which is comprised of an ultrasound coupling and a protective cover. The cartridge is able to be mounted in a receptacle which is adapted for receiving the cartridge in the ultrasonic treatment apparatus. This has the advantage that an operator can simply install a cartridge with an ultrasonic coupling medium into the patient support. The operator will not need to clean the system afterwards, and it leads to a faster workflow. The cover is adapted for being removed when the patient is in place. When the examination is finished, the operator can simply lift the cartridge and the cover out of place, and replace it with a new one.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] In the following preferred embodiments of the invention will be described, by way of example only, and with reference to the drawings in which:
[0023] FIG. 1 is a functional schematic showing an embodiment of the invention with a protective cover in place and with the protective cover removed,
[0024] FIG. 2 is a perspective view of an embodiment of the invention with the protective cover removed,
[0025] FIG. 3 is a perspective view of an embodiment of the invention that shows the positioning of the protective cover,
[0026] FIG. 4 is a perspective view of an embodiment of the invention showing the positioning of the protective cover and a patient,
[0027] FIG. 5 is a perspective, cross sectional view of an embodiment of the invention,
[0028] FIG. 6 is a perspective, cross sectional view of an embodiment of the invention,
[0029] FIG. 7 is a functional schematic showing an embodiment of the invention where the protective cover moves into a compartment when removed,
[0030] FIG. 8 is a diagram showing an embodiment of a cartridge comprised of a protective cover and an ultrasound coupling.
DETAILED DESCRIPTION
[0031] FIG. 1 shows a functional schematic showing an embodiment of the invention with a protective cover in place 100 and with the protective cover removed 102 . When the protective cover is in place 100 , the patient 106 rests on the patient support 108 . The protective cover 104 is positioned over the region 116 that transmits ultrasound. Typically an ultrasonic gel or ultrasonic gel pad is placed within this region 116 to facilitate the transmission of ultrasound. An ultrasound membrane 114 separates the region 116 from the ultrasonic transducer system 110 . The ultrasonic transducer system 110 is comprised of an ultrasonic transducer 112 , and surrounding the ultrasonic transducer is typically a medium which conducts ultrasound. This can be an ultrasonic gel or it can also be degassed water. The ultrasonic transducer 112 is able to be moved in a limited fashion. This allows the ultrasound to be focused the treatment zone 120 of the body before the treatment starts and allows the adjustment of the treatment zone 120 during treatment. The treatment zone 120 is defined as the region of the body that is treated with the ultrasonic treatment. However, the actuation of the transducer 112 is not unlimited. The patient 106 needs to be positioned properly over the transducer 112 .
[0032] The protective cover 104 protects the ultrasound membrane 114 and also any ultrasonic conductive material such as a gel pad that may be within the region 116 for transmitting ultrasound. Typically the patient 106 is positioned relative to the patient support 108 so that the ultrasound transducer 112 can properly treat the treatment zone 120 . To confirm this, the operator typically puts the patient into a medical imaging zone 134 where medical imaging is performed. If the patient is in the proper position, then the protective cover 104 is removed. However, if the protective cover 104 is able to be removed while the patient is inside the imaging apparatus, then this is straight forward, the protective cover 106 is simply removed. If this is not the case, then the patient is brought out of the imaging device and removed from the medical imaging zone 134 . The protective cover 104 is removed and the patient 106 goes back inside of the imaging apparatus. This is particularly the case when an MRI or CT system is used to treat or to guide the treatment process. The patient 106 can easily be repositioned if the position, as checked with the imaging system, is not correct. An advantage is that and ultrasonic conductive material such as a gel pad is not damaged during the repositioning of the patient 106 .
[0033] 102 shows the same embodiment after the operator has removed the protective cover 104 and the patient is inside of a medical imaging zone 134 which is being used to guide the treatment process. Visible is the ultrasound 118 being transmitted from the transducer 112 from the ultrasonic transistor system 110 through the ultrasound membrane 114 and through the region 116 for transmitting ultrasound through the skin and body of the patient 106 to the treatment zone 120 . The treatment zone 120 can be adjusted within the patient 106 by moving the transducer 112 .
[0034] FIG. 2 shows an embodiment of a patient treatment bed for an MRI system 200 . The patient support 108 , the region for transmitting ultrasound 116 and the ultrasound membrane 114 are visible in this Figure. In this particular embodiment an ultrasonic gel pad would be placed in the region formed by 116 and the patient would lie on the table. Mounting brackets 122 for holding MRI antennas and also for restraining the patient when he or she is being treated are located on either side of the region 116 .
[0035] FIG. 3 shows the same embodiment of the invention 300 as is shown in FIG. 2 . It shows two sliding protective covers 104 in place. One cover covers half of the region 116 for transmitting ultrasound. One cover 104 has been partially removed to illustrate where the split line between the two covers could be. The split line is the position where the two covers meet.
[0036] FIG. 4 shows the same embodiment of the invention 400 as is shown in FIG. 2 . In this Figure a cushion 136 is shown as being on top of the protective covers 104 . On top of the cushion and the patient support 108 is a patient. The patient 106 is positioned so that ultrasound is able to enter the body of the patient 106 during treatment.
[0037] FIG. 5 shows a perspective cross-sectional view of the same embodiment of the invention 500 as is shown in FIG. 2 . This embodiment is comprised of the patient support 108 on top of the patient support are two protective covers 104 . The patient rests upon the patient support 108 and the protective covers 104 . One protective cover has been partially removed to illustrate the split line between the two covers. Beneath the protective cover is the region for transmitting ultrasound 116 . Within the region 116 an ultrasound coupling 124 is visible. In this diagram the ultrasound coupling is a gel pad. Not visible in this Figure is the cushion which is between the patient and the patient support 108 or between the patient and the protective covers 104 . Beneath the gel pad is the ultrasound membrane 114 . The ultrasound membrane separates 114 the ultrasound coupling 124 from the ultrasound transducer system 110 . The ultrasound transducer system 110 is comprised of the water box 126 , the ultrasonic transducer 112 . The water box contains an ultrasound transmitting medium such as degassed water. Within the ultrasonic transducer system 110 is the ultrasonic transducer 112 . This is an ultrasonic transducer and as can be seen in the Figure has a curved shape which is used for focusing ultrasound to a particular point within the body. This ultrasonic transducer 112 can be moved to allow the treatment of different zones within the body during a particular treatment process. The actuators for the ultrasonic transducer are not shown in this Figure.
[0038] FIG. 6 shows a perspective cross-sectional view of an embodiment of the same embodiment of the invention 600 as is shown in FIG. 2 . This is the same view as FIG. 5 , but from a different angle. In this Figure, the patient support 108 is visible. On top of the patient support is a cushion 128 and resting upon the cushion is a patient 106 . The patient also rests upon the protective covers 104 . The cushion has a sloped surface 130 which is used to partially support the weight of the patient. This sloped surface 130 on the cushion helps to distribute the weight of the patient 106 and reduces the amount of force placed on the protective covers 104 . This sloped surface 130 reduces the amount of weight on the protective covers 104 , and allows the protective covers 104 to be slid out and removed more easily. The sloped surface 130 also provides a comfortable support for the patient during the examination and aids in properly positioning the patient relative to the ultrasonic transducer system 110 . Beneath the protective cover 104 , is the region 116 for transmitting ultrasound. This region is protected by the protective cover 104 . Inside the region 116 is an ultrasound coupling 124 . As in the last Figure, this particular ultrasound coupling is a gel pad. The ultrasound coupling 124 is resting upon an ultrasound membrane 114 which separates the ultrasound coupling 124 from the water box 126 of the ultrasonic transducer system 110 . On either side of the region 116 are mounting brackets 122 . Again these mounting brackets are used to hold an MRI antenna, and can also be used to restrain the patient. This is an important feature, because a patient restraint aids in forming a proper path for the ultrasound between the patient and ultrasonic transducer system. A patient restraint would hold the patient against and any ultrasonic conductive material such as a gel pad that may be within the region 116 .
[0039] In FIG. 6 , the patient position is checked and is carefully positioned on top of the gel pad. The patient can be asked to tilt to both sides while the protection plates are pulled away. In this way the contact with an ultrasound coupling can be done in a controlled way. Without the protective cover, there is a risk that the gel pad will be destroyed or that air bubbles get in between gel pad or gel pad and mylar window during the positioning of the patient.
[0040] FIG. 7 shows a functional schematic showing an embodiment of the invention 700 where the protective cover is able to move into a compartment in the patient support 108 . In this Figure the patient support 108 is visible. Located within the patient support 108 are compartments 132 . These can either be compartments which are able to accept and cover the protective covers 104 or they can simply be depressions in the patient support 108 which the protective covers 104 can move into. Arrows mark the direction of motion that the protective covers 104 take and show how they slide into the compartments 132 . Beneath the protective covers 104 is located a region 116 which is for transmitted ultrasound. Between the region 116 is an ultrasound membrane 114 which allows ultrasound to be transmitted from an ultrasonic transducer system 110 to the region 116 . The ultrasonic transducer system is mounted beneath the membrane 114 . Inside the ultrasonic transducer system 110 is the ultrasonic transducer 112 . The ultrasonic transducer as in the other embodiments is used to provide the patient with an ultrasonic treatment 112 .
[0041] FIG. 8 is a diagram showing an embodiment of a cartridge 800 comprised of a protective cover 104 and an ultrasonic coupling 124 . 800 shows the top view of the cartridge and 802 shows a side view of the cartridge. In this embodiment of the cartridge the cartridge top is covered by two slideable plates which comprise the protective cover 104 . Arrows mark how the protective cover would slide away. This cartridge is designed to be placed into a region for transmitting ultrasound 116 such as shown in the embodiment in FIG. 7 .
LIST OF REFERENCE NUMERALS
[0042]
[0000]
100
Embodiment of an ultrasonic treatment
apparatus with the protective cover installed
102
Embodiment of an ultrasonic treatment
apparatus with the protective cover removed
104
Protective cover
106
Patient
108
Patient support
110
Ultrasonic transducer system
112
Ultrasonic transducer
114
Ultrasound membrane
116
Region (for transmitting ultrasound)
118
Ultrasound waves
120
Treatment zone
122
Mounting bracket
124
Ultrasound coupling
126
Waterbox
128
Cushion
130
Sloped surface
132
Compartment
134
Medical imaging zone
200
Embodiment of an ultrasonic treatment apparatus
300
Embodiment of an ultrasonic treatment apparatus
400
Embodiment of an ultrasonic treatment apparatus
500
Embodiment of an ultrasonic treatment apparatus
600
Embodiment of an ultrasonic treatment apparatus
700
Top view of cartridge
800
Top view of cartridge
802
Side view of cartridge
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An ultrasonic treatment apparatus comprised of: a patient support for supporting a patient, an ultrasound transducer system for ultrasonic treatment of the patient, a region formed in the patient support operable for transmitting ultrasound from the ultrasound transducer system to a treatment zone in the patient, a protective cover for covering the region, and wherein the protective cover is adapted to be removed from the region while the patient is positioned relative to the treatment zone such that the treatment zone is able to receive treatment from the ultrasound transducer system.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. § 120 as a Continuation of U.S. patent application Ser. No. 09/337,595 filed Jun. 21, 1999 now U.S. Pat. No. 6,615,830, which is a Continuation of U.S. patent application Ser. No. 08/810,332 filed Feb. 27, 1997, now U.S. Pat. No. 5,937,851.
FIELD OF INVENTION
The present invention relates to providing a respiratory mask with a two-piece swivel conduit that uses the rotating bearing of its swivel design to permit and preferably direct carbon dioxide (CO.sub.2) laden exhaust from the patient breathing circuit.
BACKGROUND OF THE INVENTION
A variety of delivery systems are known that deliver gas at positive pressure for consumption by the user. The uses and applications of such systems vary. Some such systems have been developed for the treatment of sleep apnea.
Sleep apnea syndrome is an episodic upper airway obstruction during sleep. As a consequence, there is repeated interruption of sleep in the patient. Positive airway pressure (PAP) devices have been developed to treat this disorder. A typical PAP device comprises a flow generator (e.g., a blower) which delivers gas via a delivery conduit to a patient interface, such as a mask.
Several types of respiratory face masks for delivering gas to a patient are known. One such mask incorporates ports in the body of the mask to provide an exhaust leak to purge the system of CO.sub.2 laden air. However, several drawbacks are associated with ports in the body of the mask. For example, air exiting the mask ports may create noise or blow on the patient, causing discomfort.
Respironics, Inc. of Murrysville, Pa. has developed and manufactured a swivel conduit having exhaust vents under the name Whisper Swivel® Exhalation Port. See FIG. 1 a . This two-piece swivel conduit not only provides a swivel connection between the mask and the delivery conduit but also includes a plurality of downwardly directed exhaust slits. The slit configuration of the vents acts to reduce noise and direct the CO 2 laden exhaust away from the patient.
SUMMARY OF THE INVENTION
The improved swivel conduit rotatably connects a patient mask to the delivery conduit of the present invention of a positive pressure air supply. The improved design provides an exhaust vent for purging the system of CO 2 laden air that utilizes the rotating bearing of its two-piece design. A baffle chamber in the design reduces the intensity of the sound generated. As CO 2 laden exhaust exits the swivel conduit, it is directed away from the patient mask and down the outside of the delivery conduit via a slit pattern on the swivel conduit. The unique two-peice bearing design may be easily disassembled for cleaning.
The swivel conduit design directs CO 2 laden expiratory exhaust away from the patient in a diffused air flow stream along the delivery conduit. This diffused air flow provides for a less perceptible sensation to the patient or sleeping partner.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will become more readily apparent from the following description of preferred embodiments thereof shown, by way of example only, in the accompanying drawings, wherein:
FIG. 1 a is an exploded perspective view of a Whisper Swivel® device assembled with a respiratory mask and delivery conduit;
FIG. 1 b is an exploded perspective view of a swivel conduit according to a first embodiment of the present invention assembled with a respiratory mask and delivery conduit;
FIG. 2 is an exploded perspective view of the swivel conduit device according to a first embodiment of the present invention;
FIG. 3 is a cross-sectional view of the swivel conduit according to the first embodiment of the present invention;
FIG. 4 is top plan view of the mask connection piece according to the first embodiment of the present invention;
FIG. 5 is a cross-sectional view of the swivel conduit according to a second embodiment of the present invention;
FIG. 6 is a cross-sectional view (rotated 45° as compared to FIG. 5 ) of the swivel conduit according to a third embodiment of the present invention;
FIG. 7 is a cross-sectional view of the swivel conduit according to a fourth preferred embodiment of the present invention; and
FIG. 8 is a cross-sectional view of the swivel conduit according to a fifth embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
There is generally indicated at 10 in FIG. 1 a swivel conduit of conventional Whisper Swivel® Exhalation Port device manufactured by Respironics, Inc. Swivel conduit 10 has a mask connection piece 12 , which is received within one end of an L-shaped conduit 14 attached to a respiratory mask 16 , and a delivery conduit piece 18 , which is received within one end of a delivery conduit 20 , to deliver pressurized air from a positive airway pressure device or other ventilatory device (not shown). A plurality of parallel slits 22 on the mask connection piece 12 are directed downwardly towards the delivery conduit end 24 of the swivel conduit 10 to permit purging of CO 2 laden expiratory exhaust. The mask connection piece 12 and the delivery conduit piece 18 are rotatably coupled to each other, thus, allowing the mask 16 to rotate relative to the delivery conduit 20 .
FIGS. 1 b , 2 , 3 and 4 illustrate a first embodiment of an improved swivel exhaust device 100 . The improved two-piece design has a mask connection piece 112 , which is received within one end of an L-shaped mask conduit 14 , and a delivery conduit piece 114 , which is received within one end of the delivery conduit 20 . The mask connection piece 112 and the delivery conduit piece 114 are rotatably coupled to each other. Discharge of CO 2 laden expiratory exhaust is permitted through the clearance 116 between the mask connection piece 112 and the delivery conduit piece 114 .
The mask connection piece 112 generally comprises a tubular mask connection end 118 which is received in the L-shaped mask conduit 14 , an intermediate stepped portion 120 having a larger diameter than the mask connection end 118 , and a radial exhaust end 122 opposite the mask connection end 118 . The stepped portion 120 is joined to the mask connection 118 end by a sloped portion 124 whose diameter increases from the mask connection end diameter to that of the stepped portion diameter. The exhaust end 122 also has a sloped portion 126 in which the diameter increases to that of an annular portion 128 having a diameter larger than the stepped portion diameter. This design of the mask connection piece 112 helps direct CO 2 laden exhaust out and away from the device 100 . Raised portions 130 on the interior surface of the sloped portion 126 and annular portion 128 of the exhaust end 122 form a slit pattern which further directs CO 2 laden exhaust away from the patient ( FIG. 4 ). There are preferably three narrower raised portions 130 and one wider raised portion 132 . As CO 2 laden exhaust exits the device 100 , it is directed away from the patient mask 16 via the slit pattern down the outside of the delivery conduit 20 . In use, the wider raised portion 132 can be positioned nearest the patient side of the mask connection piece 112 so that CO 2 laden exhaust is directed away from the patient.
The exterior surface of the sloped 126 and annular 128 portions of the exhaust 122 end have raised serrations 134 to prevent intentional blocking of the CO 2 laden exhaust. However, the exterior surface in the preferred embodiment is formed without the serrations 134 .
The delivery conduit piece 114 includes a tapered delivery conduit 136 end, which is received within the delivery conduit 20 , and a swivel connection end 138 , which is rotatably received within the mask connection end 118 of the mask connection piece 112 . The swivel connection end 138 preferably has four longitudinal slots 140 forming four retaining arms 142 , 144 . Two of the retaining arms 144 that are opposite each other preferably are longer than the other two retaining arms 142 . All four arms 142 , 144 have radial outwardly projecting segments 146 to retain the delivery conduit piece 114 within the mask connection piece 112 . By pressing inwardly on the radial segments 146 of the two longer retaining arms 144 , the mask connection piece 112 and the delivery conduit piece 114 may be easily separated. The delivery conduit piece 114 has a locating portion 148 joining an intermediate stepped portion 150 and the swivel connection end 138 , and an exhaust portion 152 disposed between the stepped portion 150 and the delivery conduit end 136 . When the two pieces 112 , 114 are assembled, the two longer retaining arms 144 form cantilever springs which load, center and locate the sloped portion 124 of the stepped portion of the mask connection piece 112 against the locating portion 148 of the delivery conduit piece 114 .
The exhaust portion 152 of the delivery conduit piece comprises a sloped portion 154 of increasing diameter and an annular portion 156 of a diameter larger than the stepped portion diameter. The area between the stepped portions 120 , 150 of the mask connection piece 112 and the delivery conduit piece 114 forms a baffle chamber 158 through which the CO 2 laden exhaust flows. The baffle chamber 158 gradually reduces the noise of the CO 2 laden exhaust being purged from the device 100 .
Alternative embodiments are shown in FIGS. 5-8 with the embodiment of FIG. 7 being the preferred embodiment. Like elements will be designated by like reference numerals.
A swivel conduit 200 in accordance with a second embodiment of the present invention is shown in FIG. 5 . In this embodiments, the stepped portion of the delivery conduit piece 214 includes a raised baffle 250 to reduce noise. In this embodiment, as well as in the embodiments illustrated in FIGS. 6 and 7 , the two shorter retaining arms 242 preferably do not have radial segments. Alternately, in an unillustrated embodiment, all retaining arms are the same longer length with the two arms which are pressed inwardly for disassembly having locating notches.
A swivel conduit 300 in accordance with a third embodiment of the present invention is shown in FIG. 6 . In this embodiment 1 spaced radial holes 360 are provided (preferably four) in the stepped portion 350 of the delivery conduit piece 314 to provide an additional path for CO 2 laden exhaust between the interior of the delivery conduit piece 314 and the baffle chamber 358 . Hole bosses 362 protrude inwardly to divert fluids or secretions around the holes. In this embodiment, CO 2 laden exhaust flow is determined by both the holes 360 and the clearance 316 between the mask connection piece 312 and the delivery conduit piece 314 .
In a swivel conduit 400 of a fourth preferred embodiment illustrated in FIG. 7 of the present invention, the delivery conduit piece 414 includes a baffle portion 452 as described in accordance with FIG. 5 . Also, each of the longitudinal slots 440 of the swivel connection end 438 ends in a hole 464 . These holes 464 are preferably angled for manufacturing purposes but could be disposed radially. These holes 464 provide an improved exhaust entrance to the baffle chamber 458 .
In a fifth embodiment 500 of the present invention illustrated in FIG. 8 , the mask connection piece 512 also comprises an L-shaped portion 566 for attachment to the respiratory mask 16 , thus, reducing the need for a separate L-shaped conduit 14 . In this design, a single retaining arm 542 attaches the pieces 512 and 514 together. Likewise, it is contemplated that the delivery conduit piece 514 could be unitarily formed with the delivery conduit 20 .
The present invention provides several advantages over that of the prior art. Its unique design provides optimum comfort through improved exhaust rates and reduced noise. The pieces, which can be formed by injection molding 1 do not require additional processing, thus reducing manufacturing costs. The two-piece design is easily disassembled for cleaning and discourages exhaust vents from being sealed off. The swivel action also allows for the unplugging of secretions.
Although the invention has been described in detail for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention as it may be limited by the claims.
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A swivel exhaust conduit for rotatably connecting a patient mask to the delivery conduit of a positive pressure air supply. The swivel exhaust conduit design provides an exhaust port that utilizes the rotating bearing of the swivel conduit's rotating two-piece design for permitting and directing exhaust of CO 2 laden air. A baffle chamber formed in the clearance of the two pieces provides an area where noise is reduced. As CO 2 laden exhaust exits the swivel exhaust conduit, it is directed away from the patient mask and down the outside of the delivery conduit via a slit pattern on the swivel conduit.
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BACKGROUND OF THE INVENTION
[0001] This invention relates, in general, to an collapsible, wheeled cart, and, in particular, to a two wheeled cart take can be collapsed for transport and storage, and used to transport decoys, rifles, game and other items related to hunting.
[0002] Field or shore hunting for waterfowl requires a large number of decoys and associated equipment. Decoys are bulky. Transporting a large number of decoys and associated hunting equipment a significant distance to and from the hunting field is very difficult. Furthermore, today's waterfowl are more conditioned and wary then previous generations. In many cases, to successfully hunt today's waterfowl requires not only a great number of decoys, but a great number of ultra-realistic full-body decoys. These full-body decoys are very voluminous and therefore transportation of a number of these bulky decoys poses an even a greater difficulty than encountered in the past with more compact silhouette and shell decoys. The problems associated with waterfowl hunting and the need to transport decoys and associated gear are old and well known. As a result, there have been a number decoy carts of designed and a variety of utility, hunting, and game carts employed for decoy transportation with mixed success.
[0003] Previously hunters have used a wide variety of vehicles such as deer carts, wheel barrows, trash cans, 3-wheel running carts, “flat bed” carts, folding garden carts, children's wagons and various homemade carts. A whole host of wheeled contrivances have been used, mostly with unsatisfactory results. Blog sites commenting on the topic of decoy carts illustrate the frustration that exists with existing carts, and a search for a satisfactory solution to the need for transporting bulking decoys and waterfowl gear over rough terrain.
DESCRIPTION OF THE PRIOR ART
[0004] In the prior art various types of collapsible carts for transporting game and similar items have been proposed. The following prior art describes previous devices related to the instant invention.
[0005] U.S. Pat. No. 3,222,100 issued Dec. 7, 1965, to Lindzy for a Personnel or Game Carrier. Lindzy shows a game cart frame that disconnects at the middle of the cart to allow the frame to be longitudinally folded via the pivoted wheel supports, and has detachable wheels. This allows the cart to be reduced to a low profile configuration for transport and storage.
[0006] U.S. Pat. No. 3,860,254 issued Jan. 14, 1975, to Wegener for a Foldable Packer. Wegener shows a cart which folds in the longitudinal direction. The frame is pivoted at the axle, and has upper braces to hold it in the unfolded position. The upper braces are pivoted in the middle to allow folding, and are locked in the unfolded position by a sliding sleeve which covers the pivot joints. This sliding sleeve is much different than the slider in the instant invention.
[0007] U.S. Pat. No. 5,785,334 issued Jul. 28, 1998, to Robinson for a Bicycle Towable Collapsible Cart. Robinson shows a folding cart with a frame mounted flexible container that is similar to the flexible container of the instant invention.
[0008] U.S. Pat. No. 7,032,921 issued Apr. 25, 2006, to Swanner for a Cart to Transport Equipment or the Like. Swanner shows a cart which partially folds in the longitudinal direction and has detachable wheels.
[0009] U.S. Pat. No. 7,172,207 issued Feb. 6, 2007, to Henry for a Collapsible Cart. Henry shows a cart that folds in the transverse direction. This is accomplished by the use of telescoping uprights on both sides of the frame.
SUMMARY OF THE INVENTION
[0010] The instant invention is directed to the need for an improved economic, stable, lightweight, two-wheeled hand cart for the transportation of a large number of bulky waterfowl decoys and associated hunting gear into the field over rough terrain. The cart is easily foldable for compact storage, portability, field concealment, and shipping. The cart also functions in stretcher fashion to carry the load, with or without the wheels, when terrain conditions render wheels ineffective, or for when the loaded cart needs to be lifted over obstacles en route, or into or out of a vehicle or storage area.
[0011] It is an object of the present invention to provide a new and improved folding hand cart for transporting large numbers of bulky decoys and game across rough terrain by two people.
[0012] It is an object of the present invention to provide a new and improved cart with removable wheels which can be easily and quickly folded to a smaller profile for transport and storage.
[0013] It is an object of the present invention to provide a new and improved cart with a flexible container to hold the decoys during transport, and to prevent them from spilling out.
[0014] It is an object of the present invention to provide a new and improved cart with multiple gun scabbards for hands free transport of guns.
[0015] It is an object of the present invention to provide a new and improved cart with pockets to contain ammunition and other equipment for transport.
[0016] It is, an object of the present invention to provide a new and improved cart with load stability provided by a low cart height to wheel base width ratio and a low loaded center of gravity.
[0017] It is an object of the present invention to provide a new and improved cart having ease of rollability by the use of large diameter tires.
[0018] It is an object of the present invention to provide a new and improved cart that is lightweight by the use of a minimal structure, efficient truss frame design, and construction with lightweight tubular members.
[0019] It is an object of the present invention to provide a new and improved cart having economic construction by efficient design, ready availability of materials, and with minimum artisan technical skill.
[0020] It is an object of the present invention to provide a new and improved cart having ease of extension or folding by manual insertion or removal of a few self securing fasteners without requiring the use of tools.
[0021] It is an object of the present invention to provide a new and improved cart which is readily broken down into its component members for compact shipping.
[0022] It is an object of the present invention to provide a new and improved cart with increased strength provided by the overall design arrangement, a central frame that bears all the cart forces and moments, and the strength of materials utilized.
[0023] It is an object of the present invention to provide a new and improved cart which can used to carry a load stretcher fashion.
[0024] These and other objects and advantages of the present invention will be fully apparent from the following description, when taken in connection with the annexed drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is an overall view of the decoy cart.
[0026] FIG. 2 is a view of the central frame.
[0027] FIG. 3 a - 3 h show alternative central frame geometries.
[0028] FIG. 4 is a view of the slider.
[0029] FIG. 5 is a view of the frame.
[0030] FIG. 6 a - 6 f are views of alternative frame geometries.
[0031] FIG. 7 is a view of the flexible container.
[0032] FIG. 8 is a view of an alternate flexible container.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0033] The preferred embodiment herein described is not intended to be exhaustive or to limit the invention to the precise form disclosed. It is chosen and described to best explain the invention so that others, skilled in the art to which the invention pertains, might utilize its teachings.
[0034] Referring now to the drawings in greater detail, FIG. 1 shows an overall view of the cart 1 . A central frame 2 is located in the center of the cart 1 . Extending fore and aft of the central frame 2 are two identical frame sections 3 . Each frame section 3 is pivotally mounted to the lower end of the central frame 2 , and also pivotally mounted to a slider 4 , which is slidably mounted near the upper end of the central frame 2 . When the slider 4 is fixed in the upper position, the frame sections 3 are extended into their operational configuration. When the slider 4 is lowered to a low position on the central frame 2 , the frame sections 3 fold into a storage position. Wheels 5 are rotatably and removably mounted to the lower end of the central frame 2 . Utility straps 6 are mounted to the top end of the central frame 2 . A flexible container 7 is mounted on the frame sections 3 .
[0035] FIG. 2 shows the details of the central frame 2 . In the preferred embodiment, the central frame 2 is a square U-shaped tubular frame 8 . The tubular frame 8 has a transverse lower horizontal member 9 . Parallel gusset plates 10 are rigidly attached to each end of the lower horizontal frame member 9 by welding, fasteners, or other known connection means. Parallel upright frame members 11 are rigidly attached to the transverse lower horizontal member 9 by welding, fasteners, or other known connection means. An axle 12 is mounted on the central frame 2 by passing through the center of the parallel upright frame members 11 . The axle 12 bears on the holes in parallel upright frame members 11 . The axle 12 might also take the form of two stub axles (not shown) which extend only part way into the transverse lower horizontal member 9 . A pair of wheels 13 are pivotally and removably mounted to the opposite ends of the axle 12 . The ends of the axles 12 are provided with holes 14 , through which fasteners 15 are connected to keep the wheels 13 on the axle 12 . The fasteners 15 are removed from the holes 14 when the wheels are removed for storage or transport. A plurality of adjustable utility straps 6 are mounted to the tops of the upright members 11 and are used to secure a variety of loads (not shown) to the cart 1 . The utility straps 6 can be provided with couplers 16 for quick connection and disconnection. The utility straps 6 may also be provided with hook and loop type fasteners (not shown) such as Velcro™ hook and loop fasteners.
[0036] FIGS. 3 a - 3 h show alternative geometries for constructing the central frame 2 . FIG. 3 a shows the central frame with a square U-shaped geometry, which is described above. FIG. 3 b shows a central frame with an inverted square U-shaped geometry. In this variant, the lower horizontal frame member 9 has been relocated to the top of the upright members 11 . FIG. 3 c shows a central frame with a bent U-shaped geometry. In this variant the transverse lower horizontal member 9 and the upright members 11 are constructed from a single tubular member 17 which has been bent into a U-shape. FIG. 3 d shows a central frame with an inverted bent U-shaped geometry. FIG. 3 e shows a central frame with a truss geometry. In this variant, the transverse lower horizontal member 9 has been replaced with two truss members 18 . FIG. 3 f shows a central frame with a half-truss geometry. In this variant, two half truss members 19 have been connected between the transverse lower horizontal member 9 and the upright members 11 . FIG. 3 g shows a central frame with a solid geometry. In this variant, the transverse lower horizontal member 9 and the upright members 11 have been replaced with a solid sheet of material 20 . FIG. 3 h shows a central frame with an H-shaped geometry. In this variant, the transverse lower horizontal member 9 has been relocated to the center of the upright members 11 .
[0037] FIG. 4 shows one of the sliders 4 . Each slider 4 is comprised of two parallel plates 21 . Each of the plates 21 has several openings. The central openings are provided for fasteners 22 which connects the sliders 4 to the uptight members 11 . Keepers 22 a are provided on the end of each fastener 22 which loops around the upright members and connects to the opposite end of fastener 22 to holder the fastener 22 in place. The end openings are provided for fasteners 23 which pivotally connect the slider 4 to the frame sections 3 . The upper intermediate openings are provided for bolts 24 , which extend through one plate 21 , through spacers 25 , and then the second plate 21 , the whole of which being secured with nuts 26 . Other types of fasteners may be used instead of bolts 24 and nuts 26 . The lower intermediate openings are provided for bolts 27 , which extend through plates 21 and on which rollers 27 a are mounted. When the sliders 4 are mounted on the upright members, the rollers 27 a provide for smooth movement between the operational and storage positions of the frame sections 3 .
[0038] FIG. 5 shows details of the frame sections 3 . The frame sections 3 are symmetrically mounted fore and aft of the central frame 2 . The components of the frame sections 3 are preferably made of light weight tubular material, such as aluminum tubing. The upper frame members 28 are pivotally connected to the sliders 4 by fasteners 23 . The lower frame members 29 are pivotally connected to the gusset plates 10 by fasteners 30 . The opposite end of the lower frame members 29 are pivotally connected to brackets 31 by fasteners 32 . The brackets 31 are connected to the upper frame members 28 by fasteners 33 . Cross members 34 extend transversely between the brackets 31 , and are connected to either the brackets 31 or the upper frame members 28 by fasteners 35 . Alternatively, the lower frame members 29 and the cross member 34 may be constructed as a single U-shaped frame member (not shown). The end of the upper frame members 28 opposite the connection to the sliders 4 extend beyond the connection with the lower frame members 29 to form handles 36 . The cross members 34 may extend beyond the upper frame members 28 to provide additional handles 37 . The flexible container 7 is supported by upper frame members 28 , cross members 34 and the transverse lower horizontal member 9 .
[0039] FIGS. 6 a - 6 z show frame geometry variations. FIG. 6 a shows the truss geometry of the preferred embodiment described previously. FIG. 6 b shows a King Post truss geometry in which the lower frame members 29 are positioned above the upper frame members 28 . FIG. 6 c shows a cabled stayed truss geometry in which the lower frame members 29 are removed and replace with cable stays 40 . FIG. 6 d shows a cantilevered truss geometry in which the lower frame members 29 are removed, and the upper frame members 28 are made thicker near the central frame 2 . FIG. 6 e shows an alternative truss geometry in which the upper frame members 28 end at their connection with the lower frame members 29 , and the lower frame members 29 extend beyond their connection with the upper frame members 28 to form handles 41 . FIG. 6 f shows a scissors truss geometry in which upper frame members 28 angle downward to cross lower frame members 29 . The upper frame members 28 and the lower frame members 29 are pivotally connected at their center points. The ends of the upper frame members 28 and the lower frame members 29 are pivotally connected to end uprights 42 .
[0040] FIG. 7 shows the construction of the flexible container 7 . The flexible container 7 is suspended from upper frame members 28 and cross members 34 , and rests on the transverse lower horizontal member 9 . The body 43 of the flexible container 7 is constructed of a strong and light material such as nylon, and may be a solid or a net-like fabric. The body 43 is provided with six suspension tubes 44 through which the upper frame members 28 and cross members 34 are inserted. Four external tubes 38 are provided on the bottom of the bag 7 . Tube inserts 39 are inserted into the external tubes 38 to provide support for the load. Tube inserts 39 are made of a light weight material such as PVC pipe or aluminum tubing. The external tubes 38 may extend across the width of the bag or may be formed as short sections on each side of the bag. More than four external tubes 38 and tube inserts 39 may be used if desired. A wear liner 49 is attached to the bottom of the body 43 to resist wear from the transverse lower horizontal member 9 . Grommets 50 are provided at the ends of the wear liner 49 for the purpose of fastening the body 43 to the transverse lower horizontal member 9 . A cord (not shown) or other fastening means can be passed through the grommets 50 to attach the body 43 to the transverse lower horizontal member 9 . End pockets 51 are attached to the ends of the body 43 by sewing or other suitable fasteners. The top openings of the pockets 51 are sealed with hook and loop type fasteners (not shown) such as Velcro™ hook and loop fasteners, or other suitable fasteners. Scabbards 52 are suspended from the longitudinal suspension tubes 44 . The scabbards 52 are used for carrying guns and other hunting equipment. The openings of the scabbard may be sealed with hook and loop type fasteners (not shown) such as Velcro™ hook and loop fasteners, or other suitable fasteners.
[0041] FIG. 8 shows a second embodiment of the flexible bag 7 . Extending downward from the suspension tubes 44 are twelve support straps 45 , six on each side. The support straps 45 may be sewn or otherwise fastened to the body 43 . The lower ends of the support straps 45 are connected to cross supports 46 by fasteners 47 . The cross supports 46 pass through grommets 48 in the bottom of the body 43 and serve to support the weight of the decoys, game and other items carried in the flexible container 7 . A third embodiment of the flexible bag 7 uses an internal frame (not shown) that lays inside on the bottom the flexible bag 7 . The internal frame is made of a light weight material such as PVC pipe or aluminum tubing.
[0042] Although the Decoy Cart and the method of using the same according to the present invention has been described in the foregoing specification with considerable details, it is to be understood that modifications may be made to the invention which do not exceed the scope of the appended claims and modified forms of the present invention done by others skilled in the art to which the invention pertains will be considered infringements of this invention when those modified forms fall within the claimed scope of this invention.
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The Decoy Cart is an improved economic, stable, lightweight, two-wheeled hand cart for the transportation of a large number of bulky waterfowl decoys and associated hunting gear into the field over rough terrain. The cart is easily foldable for compact storage, portability, field concealment, and shipping. The cart also functions in stretcher fashion to carry the load, with or without the wheels, when terrain conditions render wheels ineffective, or for when the loaded cart needs to be lifted over obstacles en route, or into or out of a vehicle or storage area.
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FIELD
[0001] This patent specification relates to medical ultrasound imaging systems. In particular, it relates to an easy-to-use user interface that promotes consistent and reliable recordation of probe position during a breast ultrasound scan.
BACKGROUND
[0002] Ultrasound imaging systems have become increasingly popular for use in medical diagnosis because they are non-invasive, easy to use, capable of real-time operation, and do not subject patients to the dangers of electromagnetic radiation. Instead of electromagnetic radiation, an ultrasound imaging system transmits sound waves of very high frequency (e.g., 1 MHz to 15 MHz) into the patient and processes echoes scattered from structures in the patient's body to derive and display information relating to these structures.
[0003] Ultrasound imaging systems have been increasingly used in breast cancer screening, detection, treatment, and research. Most commonly, a breast ultrasound procedure involves the placement of an ultrasound probe over a region of interest of the breast, with the radiologist or other medical professional (hereinafter “user”) simultaneously viewing a real-time ultrasound image output on a computer monitor. The monitor also usually displays relevant text and/or graphical information near the ultrasound image for simultaneous viewing by the user. The user then presses a button to freeze the display, at which time the display may be printed on a printer or stored in digital format for later viewing and analysis.
[0004] Because much downstream analysis, interpretation, and decisionmaking may be performed based on the printed or stored information, it is crucial to ensure that the text annotation and/or graphical information relevant to the ultrasound image be both correct and properly formatted. As PACS (picture archiving and communication systems) and teleradiology (i.e., the calling up of archived images from remote locations by telephone line or internet connection) continue to increase in importance, the accurate and consistent annotation of ultrasound and other medical images will become increasingly important. Additionally, it is expected that accurate and consistent annotation of ultrasound and other medical images will become increasingly important as historical archives of breast ultrasounds and other medical images are built up over time for statistical analysis or other research purposes.
[0005] [0005]FIG. 1 shows a conventional ultrasound display 100 comprising an ultrasound image 102 , a body marker region 104 , other ultrasound parameters 106 , and a user-typed text string 108 . Body marker region 104 has the important purpose of illustrating to a subsequent viewer the position of the ultrasound probe when the ultrasound image 102 was taken. Body marker region 104 comprises left and right breast icons 110 and 112 , respectively, against which a movable probe icon 114 is manipulated by the user to reflect the current position of the ultrasound probe. Most commonly, a trackball input is used to manipulate the location of probe icon 114 relative to the breast icons, while a probe orientation knob is rotated to manipulate the orientation of the probe icon 114 relative to the breast icons. Other ultrasound parameters 106 is a text display of relevant parameters such as time, date, probe power, frame rate, etc.
[0006] User-typed text string 108 , shown in FIG. 1 by the characters “ph lesion” (representing the term “phantom lesion”), is input by the user by positioning a freely movable text cursor, using a trackball, to the relevant location on the ultrasound output 100 and then entering the relevant text portion. This is usually done to point out certain aspects of the ultrasound image 102 that may be interesting to a subsequent viewer but that may, or may not, be immediately apparent to the subsequent viewer.
[0007] Finally, ultrasound display 100 comprises a probe position text sequence 116 placed within the body marker region 104 . In conventional systems, the probe position text sequence 116 is typed in by the user, using the same or similar text input mode that is used to enter the user-typed text string 108 . The probe position text sequence 116 is shown in FIG. 1 as having been only partially input, with a cursor moving to the right as it is typed in by the user. The probe position text sequence 116 is intended to textually communicate the position of the ultrasound probe as graphically expressed by the location and orientation of the probe icon 114 . As used herein, the term “location” refers to the x-y placement of the ultrasound probe/probe icon (and also the z coordinate if applicable). The term “orientation” refers to the direction in which probe icon/ultrasound probe transducer array is pointed. The term “position” refers to the collective location and orientation information.
[0008] As known in the art, typical examples of probe position text sequence 116 may include: (i) “Left BR, Antiradial, 1:30, 3 cm,” meaning that the probe is over the left breast, is at a radius of 3 cm from the left nipple at an angle of 1:30 (i.e., 45 degrees from vertical using clock coordinates), and has an orientation in the antiradial direction (i.e., is tangent to a circle centered on the left nipple at the 1:30 location); (ii) “Left BR, Radial, 6:00, 5 cm,” meaning that the probe is located over the left breast 5 cm directly below the left nipple and is oriented in the radial direction, (iii), “Right BR, Trans, 10:00, 4 cm,” meaning that the probe is located over the right breast at 4 cm in the 10:00 direction from the right nipple and is oriented in the transverse direction (i.e., parallel to a line between the two breast nipples), (iv) “Right BR, Long, 7:00, 8 cm,” meaning that the probe is over the right breast at 8 cm in the 7:00 direction and is oriented in the longitudinal direction (i.e., parallel to the longitudinal or sagittal axis of the body), and (v) “Left BR, Oblique, 8:00, 3 cm” meaning that the probe is over the left breast at 3 cm in the 3:00 direction, and is not oriented along any standard direction. As known in the art, examples (i) and (ii) above express the orientation of the probe with respect to a radial/antiradial coordinate system, while examples (iii) and (iv) express the orientation of the probe with respect to a transverse/longitudinal coordinate system. In general, the “oblique” designation in example (v) may be used with either the radial/antiradial or transverse/longitudinal coordinate system.
[0009] One problem that arises with the system of FIG. 1 is that the user is required to alphanumerically key in the probe position text sequence 116 when such text is desired. This process can be cumbersome, can lead to user frustration, and, when many breast ultrasound scans are being recorded, can lead to user fatigue. Sonographers must routinely manipulate the ultrasound probe with one hand and operate the ultrasound system controls and keyboard with the other. The hand that manipulates the probe is often times gloved and/or encumbered by having ultrasound gel on it. With interventional procedures including biopsies and ductography, contamination may occur from blood and/or nipple discharge as well. Conventional annotation mechanics that require any keyboard entries mean that the operator either has to stop, wipe their hands, and then type with both hands, or, use a keyboard designed for two hands with a single hand. Further, unless the operator truly goes to the sink and washes thoroughly and carefully before typing on the keyboard, there is the potential for contamination of the keyboard with pathogens such as fomites. These could be passed on to later patients by the operator. Also, there is the potential for damage of the equipment by moisture from the ultrasound gel deposited on the keyboard and controls.
[0010] Moreover, any delays incurred while typing in the probe position text sequence 116 can lead to the possibility that the ultrasound probe may have moved slightly in the meantime. Due to frustration, fatigue, or other factors, the user may return to properly adjust the probe icon 114 and the probe position text sequence 116 . This can result in decreased correlation between the ultrasound image and the supporting information the printed or digitally stored copy.
[0011] Another disadvantage of the system of FIG. 1 is that different users may incorporate different text schemes for entering the probe position text sequence 116 , or the same user may use different text schemes at different times. As a result, different ultrasound output pages from the same laboratory or even the same user may differ in the format of their probe position text sequences. Especially in environments in which such information would be digitally stored, this is disadvantageous because it makes statistics gathering or other off-line automated analysis difficult to achieve across large volumes of ultrasound outputs. Given the potential future usefulness of such information in tracking historical data associated with different patients or populations, it may be important to ensure uniformity in the probe position text sequences of ultrasound output pages.
[0012] Finally, another disadvantage of the system of FIG. 1 is that even the purely graphical manipulation of the probe icon 114 may be cumbersome if the user wished the ultrasound probe position to remain in a major direction. For example, if the user is recording two successive ultrasound frames in the antiradial orientation at two different locations, then after the first frame the user must move the trackball until the probe icon is at the second location, and then must carefully re-manipulate the probe orientation knob until the probe icon is oriented in the antiradial direction. This process is unnecessarily cumbersome when it is already known that the probe icon should be in the antiradial direction at the second location.
[0013] While a completely automatic position sensing system might represent one option for providing an automatic recording of probe position information, including text-based information, it has been found that position sensing equipment can be cumbersome to use in clinical applications. Moreover, the accuracy of such systems can be reduced because the patient's breast nipples, used as reference points in the probe position display, often move around during the ultrasound procedure. This reduces the usefulness of the position sensor readouts as replacements for the medical professional's own estimation of probe position.
[0014] Accordingly, it would be desirable to provide an ultrasound system that is easier to use in terms of the textual recordation of user estimates of ultrasound probe position.
[0015] It would be further desirable to provide an ultrasound system that is easier to use in terms of orientating a probe icon along major directions while manipulating the probe icon.
[0016] It would be still further desirable to provide an ultrasound system that promotes uniformity in the formatting of probe position text sequence outputs.
[0017] It would be even further desirable to provide an ultrasound system for which the user can functionally operate the controls efficiently and ergonomically with one hand.
SUMMARY
[0018] In accordance with a preferred embodiment, a method and system for providing ultrasound probe position information corresponding to an ultrasound image of a target are provided, wherein a text sequence corresponding to a user's estimate of the position of an ultrasound probe is automatically generated based on the user's graphical manipulations of a probe icon relative to a breast icon. User inputs are received through a trackball, knob, mouse, or other graphical input device and used to adjust the position of the probe icon relative to the breast icon. The probe position text sequence is automatically generated and continuously updated as the probe icon is manipulated. Because the user is no longer required to manually key in their estimate of the probe position, they may concentrate more easily on accurate placement of the probe icon on the ultrasound display. Moreover, user fatigue associated with repeated keypad entries is avoided. Additionally, probe position text sequences are generated in a common format without unnecessary truncations or misspellings, thereby being more amenable to digital archiving and subsequent computerized access and analysis.
[0019] In one preferred embodiment, the user is permitted to select a snapping mode of operation in which the probe icon is snapped to align with a major direction of a preselected coordinate system. In one particular preferred embodiment, this snapping mode is automatically associated with the user's selection of a radial/antiradial coordinate system, for which this snapping mode has been found to be particularly useful and convenient. If the preselected coordinate system is the transverse/longitudinal coordinate system, this snapping mode is not automatically activated, for permitting a large range of oblique orientations to be recorded.
[0020] In another preferred embodiment, the user is permitted to select a classification mode of operation in which the location of the probe icon is automatically classified into one of a plurality of standardized zones based on its position with respect to a reference point, such as a nipple of the patient's breast. A text representation of this zone is included in the probe position text sequence. Optionally, the user is permitted to select a manual override mode of operation in which the probe position text sequence may be altered or appended by the user.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] [0021]FIG. 1 illustrates a prior art ultrasound display output;
[0022] [0022]FIG. 2A illustrates an exterior view of an ultrasound system in accordance with a preferred embodiment;
[0023] [0023]FIG. 2B illustrates a functional block diagram of an ultrasound system in accordance with a preferred embodiment;
[0024] FIGS. 3 A- 3 D illustrate a body marker portion of an ultrasound display output in accordance with a preferred embodiment;
[0025] [0025]FIG. 4 illustrates steps for recording probe position during a breast ultrasound scan in accordance with a preferred embodiment; and
[0026] [0026]FIG. 5 illustrates an input screen for setting alphanumeric probe position display parameters in accordance with a preferred embodiment.
DETAILED DESCRIPTION
[0027] [0027]FIG. 2A illustrates an exterior view of an ultrasound system 200 in accordance with a preferred embodiment, the ultrasound system 200 being amenable for recording probe positions during breast ultrasound scans in accordance with a preferred embodiment. In one preferred embodiment, the ultrasound system 200 is similar to an ultrasound system currently named the USI-2000™ available from U-Systems, Inc. of San Jose, Calif. It is to be appreciated, however, that many ultrasound system architectures may be readily adapted for use in accordance with the preferred embodiments.
[0028] Ultrasound system 200 comprises a chassis 202 for housing ultrasound processing hardware, an ultrasound probe 204 , a monitor 206 , and a user interface platform 208 . User interface platform 208 comprises a keyboard 210 , a trackball 212 , a series of rotatable knobs including a probe orientation knob 214 , and a plurality of user buttons or keys including a body marker key 216 and a set key 218 .
[0029] [0029]FIG. 2B illustrates a functional block diagram of an ultrasound system 250 that generally corresponds to the ultrasound system 200 of FIG. 2A. Ultrasound system 250 comprises a transducer 252 , a transmit beamformer 254 , a receive beamformer 256 , a demodulator 258 , a packetizer 260 , a digital signal processing (DSP) subsystem 262 , a system controller 264 , a protocol interface 266 , a host computer 268 , a user interface 270 , and a display 272 . Although many ultrasound system architectures may be readily adapted for use in accordance with the preferred embodiments, ultrasound system 250 is preferably similar to the those described in the commonly assigned U.S. Ser. No. 09/224,635, filed Dec. 31, 1998, and U.S. Ser. No. 09/449,095 filed Nov. 24, 1999, which are incorporated herein by reference, or to the USI-2000™ system, supra.
[0030] Transducer 252 comprises an array of transducer elements that transmits focused acoustic signals into a target responsive to signals generated by the transmit beamformer 254 . Responsive to control signals and parameters received from system controller 264 , transmit beamformer 254 generates signals that are converted into acoustic interrogation signals by transducer 252 and introduced into the target. Transducer 252 also receives acoustic echoes from the target and converts them into signals for forwarding to receive beamformer 256 . Receive beamformer 256 receives the signals and converts them into a single-channel RF signal. Demodulator 258 receives the single-channel RF signal and generates component frames therefrom, which are then packetized by packetizer 260 and fed to DSP subsystem 262 . DSP subsystem 262 performs any of a variety of image processing algorithms on the packetized component frames (e.g., filtering, image compounding, segmentation, etc.) in accordance with the flexible, programmable architecture of the ultrasound system 250 . The output image data is transferred to protocol interface 266 , but may optionally be further processed by system controller 264 . The compound output image frames are then transferred to host computer 268 which performs scan conversion on the signals for transmission to user interface 270 and ultimate display by display 272 .
[0031] In one preferred embodiment, the host processor 268 and user interface 270 comprise off-the-shelf Intel-based hardware running a Windows NT operating system, and execute instructions compiled from one or more programs written in the C++ programming language to achieve the functions described herein. However, it is to be appreciated that probe position detection and recording in accordance with the preferred embodiments may be implemented on any of a variety of computing platforms. Indeed, in one preferred embodiment, probe position detection and recording may even be implemented on a computer system separate from the ultrasound system 250 , provided that the user may simultaneously view their respective outputs, and provided that hardcopy or digital storage outputs of the separate systems may be properly associated with each other. Given the present disclosure, a person skilled in the art will be readily able to implement a computer program or group of programs for achieving the functionalities described herein.
[0032] FIGS. 3 A- 3 D show a body marker region 300 of an ultrasound display in accordance with a preferred embodiment. Body marker region 300 comprises a right breast icon 302 , a left breast icon 304 , a probe icon 306 , and a probe position text sequence 308 . In accordance with a preferred embodiment, probe position text sequence 308 is automatically and continuously generated and displayed based on the position of the probe icon 306 . Probe icon 306 , in turn, is manipulated by the user through trackball 212 and probe orientation knob 214 according to the user's estimate of the position of the actual ultrasound probe, which the user is usually holding in their other hand. Probe position text sequence 308 is generated using conventional geometrical principles together with a scaling factor that scales distances on the body marker region 300 to actual physical distances on the patient's body. Usually, a fixed approximation that the breast nipples are separated by about 30 cm will suffice for computing the scaling factor, although this distance may be user-settable.
[0033] FIGS. 3 A- 3 D represent a sequence of configurations of the body marker region 300 as the user changes the location of the probe icon 306 from its location in FIG. 3A to its location in FIG. 3D, with the user having chosen a radial/antiradial mode of operation. In this mode of operation, the probe icon 306 is automatically snapped to the closer of the radial or antiradial direction prior to display and prior to computation of the probe position text sequence 308 . If the location remains fixed while the user turns the probe orientation knob 214 continuously, the probe icon 306 will remain fixed in its orientation (radial or antiradial) as the probe orientation knob 214 subtends a small arc around its current position. However, when a threshold arc is reached, the probe icon 306 will snap ninety degrees to align with the next major direction (antiradial or radial, respectively).
[0034] In the example of FIGS. 3 A- 3 D, the probe icon 306 begins in a radial orientation at 2:00 in FIG. 3A, and the user moves the trackball to the right and slightly up such that the probe icon remains generally along the 2:00 direction with respect to the nipple of the right breast icon 302 . As the probe icon 306 moves, the probe position text sequence 308 continuously changes (see FIGS. 3B and 3C) to reflect its current position. In accordance with a preferred embodiment, the text sequence portion corresponding to the angular location only changes by preselected increments, e.g. in ½ hour or 1 hour increments. This is in recognition that the precision of the user's estimation of the angular location of the ultrasound probe will usually not be finer than these amounts. Thus, while the angular location of the probe icon 306 with respect to the nipple of the right breast icon 302 may wander somewhat from the precise 2:00 direction, the text will still read 2:00.
[0035] In the example of FIGS. 3 A- 3 D, the orientation of the probe icon 306 remains snapped to the radial direction. If the initial orientation of the probe icon 306 were in the antiradial direction, the antiradial orientation would remain regardless of probe icon location, the probe icon 306 rotating on its own so that it faces the nipple of the right breast icon. The probe icon 306 will continue to do so until the user turns the probe orientation knob 214 by an amount sufficient to snap the probe icon 306 to the radial direction. This feature has been found to particularly enhance ease-of-use of the system by reducing the required manipulation of the probe orientation knob when the user wishes the ultrasound probe to remain aligned with a major (radial/antiradial) direction.
[0036] In contrast, where the transverse/longitudinal mode is selected, the probe orientation will remain fixed with respect to the output display screen unless probe orientation knob 214 is turned. Different amounts, increments, and directions of snapping may of course be implemented without departing from the scope of the preferred embodiments.
[0037] FIGS. 3 C- 3 D show the crossover of the probe icon 306 from the right breast to the left breast. In accordance with a preferred embodiment, ultrasound system 200 automatically detects which breast icon nipple is nearer to the probe icon 306 , and uses that nipple as the reference point for generating the probe position text sequence 308 . As the probe icon 306 changes over to the left breast coordinate system, it is automatically rotated and snapped to its new radial orientation (from 2:00 to 10:00).
[0038] [0038]FIG. 4 illustrates steps taken in a method for recording probe position during breast ultrasound scans in accordance with a preferred embodiment. At step 402 , the user presses the body marker key 216 to enter into the auto text mode. At this point, the probe position text sequence will begin to continuously appear in an updated fashion in the body marker region. At step 404 , ultrasound system 200 receives location control and orientation control inputs using the graphical inputs described supra. If the user has selected the radial/antiradial mode in a setup screen described infra, the probe icon will be snapped to the nearest radial or antiradial orientation (steps 406 and 408 ). At steps 410 and 412 , the probe icon is displayed along with the automatically-computed probe position text sequence. At step 414 , if a set command is not received, further graphical user inputs are received at step 404 . If a set command is received at step 414 , step 416 is executed in which the probe icon and probe position text sequence are frozen, and the auto text mode is exited at step 418 . At this point, the user may invoke a print command or other output command to cause the screen ensemble to be printed on a printer or digitally stored. In one preferred embodiment, the user may be given the option, before or after exiting the auto text mode, of altering or appending the probe position text sequence.
[0039] [0039]FIG. 5 shows an auto text setup screen 500 in accordance with a preferred embodiment, comprising an activation toggle 502 , a coordinate system selection column 504 , an angular location precision selection column 506 , and a set button 508 . Auto text setup screen 500 conveniently allows the user, using a conventional personal-computer-like display with a mouse icon 501 , to enable/disable the auto text feature, and to pre-select the desired settings among coordinate system options and angular location precision options described supra.
[0040] In an optional preferred embodiment, the user is permitted to select a classification mode of operation in which the location of the probe icon is automatically classified into one of a plurality of standardized zones based on its position with respect to the reference point, such as a nipple of the patient's breast. A text representation of the zone is then included in the probe position text sequence. By way of example and not by way of limitation, some users prefer the annotation of Zone 1, 2, and 3 to represent successive concentric rings having widths of one-third of the radius of the breast, with Zone 1 being nearest the nipple and zone three being farthest from the nipple. A typical probe position text might read “Left BR, Antiradial, 8:00, 6 cm, Zone 2” or simply “Left BR, Antiradial, 8:00, Zone 2.”
[0041] In another optional preferred embodiment, the zone classification may also include depth information. Most commonly, this depth information would apply to a particular lesion or other important feature appearing in the ultrasound image. For example, a depth classification A, B, or C may be added to represent the anterior third, middle third, or posterior third of the region between the skin surface of the patient's breast and the pectoral muscle underneath the patient's breast. Several different methods may be used to generate this data point. In a first example, ultrasound system settings corresponding to a focus depth may be imported to compute the depth classification, it being assumed that the user will cause the lesion to be placed at the focus depth. In a second example, the user would manipulate two cursor marks superimposed on the ultrasound image itself, one at the center of the lesion and the other at the surface of the pectoral muscle. The ultrasound system would then automatically compute the proper depth classification. In a third example, a vertical profile icon having a top marker representing the skin surface and a bottom marker representing the pectoral muscle may be displayed adjacent to the breast body marker supra. The user may then place a cursor at the appropriate place between the top and bottom markers of the vertical profile icon, whereby the ultrasound system may then automatically compute a depth classification A, B, or C. The second and third examples recognize the fact that the depth of the pectoral muscle differs from patient to patient depending on their breasts size and other factors. By way of example, in this embodiment, a typical probe position text sequence might read “Left BR, Antiradial, 8:00, 6 cm, Zone 2B” or simply “Left BR, Antiradial, 8:00, Zone 2B”.
[0042] Advantageously, a system according to the preferred embodiments makes accurate and fast annotation possible with one hand. Among other benefits, this allows the operator to keep their gloved, scanning hand away from the ultrasound machine once the patient demographics have been entered and the examination has begun. This minimizes the potential for contamination of the ultrasound unit and the spread of pathogens from patient to patient. In additional to cleanliness benefits, both ergonomics and biomechanical efficiency are improved. Because there is less typing involved overall, the likelihood of biomechanical injury that can result from repetitive keyboard entry (e.g., carpal tunnel syndrome) is reduced.
[0043] Whereas many alterations and modifications of the present invention will no doubt become apparent to a person of ordinary skill in the art after having read the foregoing description, it is to be understood that the particular embodiments shown and described by way of illustration are in no way intended to be considered limiting. For example, while presented supra in the context of breast ultrasound scans, the preferred methods for recording ultrasound probe position are readily adaptable to other ultrasound applications, including pre-natal ultrasound applications, other medical ultrasound applications, non-medical ultrasound applications (e.g., for manufacturing quality control, etc.), and other medical imaging applications. Additionally, the features and advantages of the preferred embodiments are readily adaptable for wider use with PACS and teleradiology systems, supra, where images acquired elsewhere are to be further annotated on a remote workstation using a keyboard, perhaps at the time of interpretation. Therefore, reference to the details of the preferred embodiments are not intended to limit their scope, which is limited only by the scope of the claims set forth below.
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A method, system, and computer program product for providing textual ultrasound probe position information corresponding to an ultrasound image of a target is described. Based on a user's graphical manipulations of a probe icon relative to a breast icon, a text sequence corresponding to the user's estimate of the position of an ultrasound probe is automatically generated. User error and fatigue are reduced because manual keying of the probe position text sequence is no longer required, and the resulting outputs are standardized in format and therefore more amenable to archiving and electronic analysis. In one preferred embodiment, the user is permitted to select a snapping mode of operation in which the probe icon is snapped to align with a major direction of a preselected coordinate system, further enhancing ease-of-use and reducing user fatigue.
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FIELD OF THE INVENTION
This invention relates to grinding wheels, and more particularly concerns a grinding wheel having an improved resin binder of low molecular weight solid epoxy resin.
BACKGROUND OF THE INVENTION
About half of all grinding wheels made are vitrified bonded, and most of the rest are phenolic resin bonded. Wheels formulated with a liquid epoxy resin bond are the latest development. Liquid epoxy resin has superior physical characteristics as compared to phenolic resin. Among other aspects, it has higher tensile strength, less brittleness, more heat resistance, extra adhesion and better resistance to coolants. Powdered phenolic resin, however, is much easier to use in the production of wheels, and so is better suited for making a wide variety of wheel formulations.
The term "grinding wheels" refers to hard grinding elements including the standard wheel shape, cup wheel shape, mounted point shape, honing stone shape, etc. Grinding wheels are made of abrasive grains held together in a matrix by a binding material or ingredient.
The main binding ingredient is usually classified as being inorganic or organic. Inorganic binders include ceramic (vitrified) and oxychloride (magnesite). Organic binders include resins such as phenolic, shellac, epoxy, polyester and rubber. In some cases, the binder may be a combination, such as a phenolic resin and rubber. Different applications may require different binding materials.
In addition to the main binder material, other materials or fillers are often incorporated in a wheel formulation. These may be for the purpose of increased wheel strength, lubrication at the point of grind, prevention of steel chips welding to wheel face, or other such processing and operating benefits.
The major operations in the manufacturing of grinding wheels are: mixing the ingredients, molding them, firing them, and finishing them. Mixing is the operation of weighing raw materials, combining them in a mixing machine, screening them, and related steps prior to molding. Molding is the operation of placing the mix of raw materials in a steel form, and then leveling and pressing the mix to the desired thickness to form a "green" wheel which may be handled without falling apart. Firing or curing is the operation of applying heat in a kiln or oven to the molded "green" wheel in order to fuse an inorganic bond or polymerize an organic bond and producing a grinding wheel which is then cooled. Finishing is the operation of trimming the hardened wheel so as to remove material in excess of the desired final size.
The combined raw material mix for the grinding wheel generally can be classified as being dry, liquid (fluid or viscous), or a resilient solid. Most grinding wheels, whether inorganic or organic bonded, are produced from a dry mix. The abrasive grain is wetted thinly with a wetting agent--a solvent and/or resinous liquid--and then blended with a powdered binder. The binder is slightly dissolved by the wetting agent and adheres to each abrasive grain as a coating.
Inorganic or organic bonded wheels of a more specialized nature are produced from a liquid mix. The abrasive grain is coated with a mainly liquid binder.
Rubber bonded wheels are produced from slabs of resilient rubber impregnated with abrasive grain and fillers. This type of grinding wheel with a rubber mix is a minor one and has become more so in recent years.
The dry mix process of making grinding wheels generally is regarded as the most efficient and that is the reason for its predominance in the industry. It offers production and consistency advantages unmatched by the less used alternative liquid mix process.
The main production advantage of the dry mix process lies in its suitability for automation of mixing and molding. As a consequence, the labor content of the dry mix process is usually significantly lower than that with the liquid method. Large batches of powdered mix may be blended with ease in any of a number of common type industrial mixers. Because all ingredients, except for a small amount of wetting agent, are dry, the handling of them before and after mixing offers little difficulty. The equipment, including material pans, mixer blades, mixer chamber, chutes and the like, remains dry and relatively clean.
The liquid method, in most cases, does not lend itself to the same level of mixing automation, and requires more labor and complex equipment. Liquid epoxies, urethanes and some phenolics generally require the addition of curing agents, accelerators and the like. Precise proportions must be maintained. Most curing agents and accelerators are liquid, and they start resin advancement when added. Because of the viscosity, proportion sensitivity, and resin advancement, volume wheel production requires sophisticated component metering and mixing equipment. Even such equipment, however, cannot avoid many problems associated with mixing liquids with large quantities of sand-like abrasive grains. Accumulation of viscous materials, especially room temperature curing types, on equipment is a serious problem, and often requires removal by application of hazardous solvents. Wheels can be made by the liquid method by using less automated equipment but at a cost of extra labor and product inconsistency.
The dry molding operation offers labor savings over liquid methods. The dry method of molding is widely used and consists of pouring the free-flowing dry mix into a steel circular mold rotating on its vertical axis. After the proper amount of dry mix has been poured into the mold and leveled, the mold rotation is halted. A steel plate, similar to one already below the mix, is placed on top of the mix. The mold then is transferred into a hydraulic press, and the press is closed onto the mold assembly and exerts great compressive force on the wheel mix. When the mix has been compressed to the desired thickness it forms a "green" wheel, and the press ram retracts and the mold is moved onto a stripping mechanism. The stripper clamps the mold while pushing or stripping the "green" wheel upward from the mold. The mold then is moved back to its original location for the next cycle. This sequence of molding steps often is semi- or fully automatic and requires only a few moments to complete, depending on wheel size. The "green" wheel, after pressing, possesses sufficient "green" or uncured strength to withstand stripping and handling forces. It then is placed on a suitable plate or cart and transported into an oven.
Liquid molding does not have the advantage of using one mold for a rapid succession of wheels. Because the mix is wet or damp, once placed in a mold, it must stay until partly or fully cured. It has no "green" strength. Demolding may be delayed from several hours to over a day, depending on whether heat is applied. If heat is applied, extra time may be needed to cool the mold before cycling again. A number of molds are required even for modest production levels. Although a hydraulic press may not be necessary, other methods such as tamping or rolling are often used to fill the mold properly. Liquid mix must be poured into the mold carefully since trapped air bubbles can affect the quality of the finished wheel. Consistency of finished product is often a problem. If using a reactive mix, the last of the batch will have advanced somewhat by the time it is molded into a wheel. As a consequence, the last wheel of the batch may grind differently from the first.
An important feature of most grinding wheels is the porosity of the structure. Basically, a wheel is comprised of three entities: abrasive grains, a bond coating each grain and attaching it to its neighbor to form a matrix, and voids that exist between the grains of the matrix. The voids perform a useful function in the manufacturing and performance of a properly designed wheel. After curing, their similar size and frequency on all sides of the wheel indicates structure uniformity. Liquid bonded wheels can have the difficulty of the grains sinking to the bottom of the mold, leaving an excess of bonding material on top. The structure would not be considered uniform. During grinding, the voids provide space for metal chips from the object being ground to lodge temporarily. The larger the chips, the larger should be the designed voids. They also provide space for coolant to occupy, and allow the coolant to better reach the area of grind. The dry process naturally produces a porous structure. The liquid process does not, and must include special fillers that, upon burning away, leave voids in their place. The effectiveness of such fillers is often questionable.
A problem with all phenolic formulations, and most liquid epoxy formulations, is the presence of environmentally undesirable compounds. Phenolic resin bonds are based on the simultaneous use of phenolic resoles and phenolic novolacs. During a two-day curing operation at 175 degrees C., significant quantities of free phenol, formaldehyde and ammonia are released into the air. Epoxy resins generally are not an environmental problem but the curing agents can be hazardous. The most commonly used curing agents for liquid epoxies are aliphatic polyamines. These are classified as skin sensitizers, and can cause respiratory difficulties. Aromatic amines also are used for this type product and they are classified similarly as well as being a suspected carcinogen. Reactive diluents used for reducing liquid resin viscosity are sensitizing agents, and must be handled with care. Because of the nature of grinding wheel manufacturing, close physical and respiratory contact with materials in the process is nearly impossible to avoid.
Simply put, the dry process is the most effective method of designing and manufacturing grinding wheels. The resin with the best physical properties, however, is epoxy, which is a liquid in its commonly used form. Both phenolic and liquid epoxy bonds can be hazardous to workers and the environment.
SUMMARY OF THE INVENTION
This invention concerns the development of a dry process but with a unique solid epoxy resin as the binder. In addition, the bond essentially is non-hazardous.
It is an object of this invention to provide a grinding wheel with improved wear resistance, giving added value to the consumer.
It is another object of this invention to provide a wheel of greater strength which may be operated at higher speeds and at heavier grinding pressures.
It is another object of this invention to provide a wheel offering more safety to the consumer due to greater resistance to the softening effect of coolant on the binding material in the wheel.
A further object of this invention is to provide greater protection for wheel manufacturer employees, and to protect the environment by reducing or eliminating the emission of free phenol, formaldehyde and ammonia liberated during the curing of traditional phenolic resin bond wheels. The environment benefits additionally in that the energy required to cure epoxy resin bonded wheels is substantially lower than that for phenol formaldehyde (phenolic) resins.
The above objects are accomplished by the use of a powdered epoxy resin having a low molecular weight (less than 900 epoxide equivalent weight--EEW). Such an epoxy resin, polymerized by an appropriate curing agent and accelerator, functions as a more effective grinding wheel binder than phenolic resin.
In addition to the liquid epoxy binders already discussed, some binders have been made of solid epoxies. These epoxies are currently available from resin manufacturers in powdered form and are used for making light duty type wheels. These resins are of a much higher molecular weight structure, (approx. 900 to 1800 EEW). In addition, some phenolic resin bonds have been formulated with a moderate percentage of higher molecular weight solid epoxy. This epoxy additive has been found to improve the performance of certain type wheels.
The distinction between lower and higher molecular weight solid epoxies is that the lower the EEW, the better are many physical properties such as tensile strength. Resins having a lower EEW, however, also have a lower softening point since their chemical structure more resembles epoxy in its liquid state. Solid epoxies are commercially available most often in the form of thin chips. The chip size varies depending on the resin manufacturer, etc., but is approximately 0.100 inch thick and 0.2 sq inch in area.
To be useful for grinding wheel makers, the chip must be reduced in size to less than 200 mesh. Because of its lower softening point, this is more difficult to do with lower EEW resins. Special equipment and the use of liquid nitrogen while pulverizing is recommended. In addition, the lower softening point precludes the use of common modes of transportation between the resin manufacturer and the user--the wheel manufacturer. A lower molecular weight, EEW, powdered epoxy resin tends to fuse into a solid mass when exposed to high summer temperatures in much of the country. A drum of this powdered material could arrive as a hard lump if transported by truck.
Difficulty in pulverizing and transporting lower EEW powdered epoxies is one reason the solid epoxy resins pertinent to this invention have not been offered to wheel manufacturers for regular and heavy duty grinding wheel product lines. In addition, the wheel formula and bond formula are entirely different from conventional formulas. The proportion by weight of bond to fillers to abrasive grain is considerably different than with conventional wheel formulas. Also, the wheel manufacturing process is different because the lower molecular weight resin has a much lower softening point and a unique curing cycle. Because of the softening point, typical grinding wheel mixing equipment is unsuitable. Friction generated at certain points in the mixing chamber tends to melt part of the mix which then solidifies immediately into small lumps.
The novel wheel bond material comprises a low EEW, solid resin, a curing agent and an accelerator. The resin chips are crushed to a small particle size. The resin, cure agent and accelerator are weighed and then blended together in a ribbon blade mixer. They are then melt mixed in an extruder to form a paste. The extruded paste is discharged in the shape of a continuous strip and is cooled, and crushed to a chip size. The chips are frozen while being fed into a hammer mill type pulverizer and reduced in size to under 200 mesh. Although a number of steps are required to process the raw materials into the wheel bond material, average sized crusher/pulverizers, mixers and extruders process relatively large quantities of bonded material quickly.
The abrasive grains, wetting agents, bond and fillers, if any, are weighed out according to the formula for the wheels being made, and the materials are mixed in a low friction mixer. The amount of mix needed for each wheel is weighed and poured into a rotating steel mold. The wheel mix is then leveled, compressed into the shape of a wheel in the mold, stripped from the mold and placed in an oven, heated and cured in the oven, finished, inspected and marked.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a view in vertical cross section of a mold suitable for making the grinding wheels of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
A method of making a grinding wheel of the present invention comprises the steps of reducing epoxy resin chips of low molecular weight in the range of 500 to 875 EEW to a powder of less than 60 mesh in a hammer mill, batch mixing the epoxy resin powder with a powdered curing agent and a powdered accelerator to form a mixed powder, heating the mixed powder to the softening point of the epoxy resin, kneading the softened mixed powder while the heat is being applied and forcing the powder particles into close and uniform distribution in the mix to form a hot doughy mix, continuing this kneading action on the hot doughy mix and transporting it through a mixing chamber to a discharge section, discharging the hot doughy mix in the form of a ribbon mix, cooling the ribbon mix, breaking the cooled ribbon mix into thin mix chips, cooling the mix chips, pulverizing the cooled mix chips into a binder mix powder, coating abrasive grains with a wetting agent, mixing the coated grains with the binder mix powder to form a grinding wheel mixture, weighing the grinding wheel mixture to obtain a desired weight, pouring the weighed grinding wheel mixture 11 into a steel mold 13 having an inner circular wall 15 and an outer circular wall 17 and a bottom annular plate 19 which define an annular mold cavity 21, spinning the steel mold 13 on its vertical axis, leveling the grinding wheel mixture 11 in the mold 13, shutting off the spinning of the mold 13, placing a top annular plate 23 on top of the grinding wheel mixture 11 in the mold, compacting the grinding wheel mixture 11 to form a green wheel by applying hydraulic pressure for about one minute to the top plate 23 and bottom plate 19, stripping the green wheel from the mold 13 and placing the green wheel in an oven, curing the green wheel to form a grinding wheel by applying heat to the green wheel in the oven, and cooling the grinding wheel to room temperature.
As discussed above, the binder used comprises a low molecular weight epoxy resin in solid form, a curing agent, and optionally an accelerator.
Chemically, the term epoxy, epoxide in Europe, refers to a resin containing more than one a-epoxy group situated terminally, cyclicly, or internally in a molecule which can be converted to a solid through a thermosetting reaction. The most common solid epoxy categories are DGEBA, phenol novolac and cresol novolac. The solids differ from liquid epoxies in that the solids have higher molecular weights which can range from 500 EEW to 5000 EEW. The novolacs have the advantage of higher functionality and thus a higher density crosslinking potential. There are more epoxy groups per novolac molecule than for an equivalent weight DGEBA molecule.
All three solid epoxy resin types described above have been used in the production of the inventive grinding wheels. Certain categories of wheels benefit most from the physical characteristics particular to one or a blend of the three types of solid epoxy resins. The range of molecular weight selected was from 500 to 875. The preferred resin is Dow Chemical's D.E.R. 642U, a 500 to 560 EEW phenol epoxy novolac resin in solid chip form.
The above resins are hardened by any one of many curing agents. Curing agents are available in liquid and solid forms. Some curing agents begin the polymerization process almost immediately while others are more latent and require the application of heat to harden the epoxy. The preferred curing agent is latent and is Pacific Anchor's Amicure CG-1200, a dicyandiamide in finely powdered form.
Certain resin/curing agent systems require the use of an accelerator in order to reach optimal polymerization or to do so in less time or with less application of heat. For all three reasons, it is advisable to include a curing agent when using an epoxy/dicyandiamide system. The preferred accelerator is Omicron's Omicure 24, an immidizole in powdered form.
The above three bond materials must be combined according to a predetermined ratio and in a manner insuring they have close and uniform physical contact during the curing process. A number of processes may be utilized for the combining of these materials, including dry blending, melt mixing in an extruder and the solution technique.
For a high performance product such as grinding wheels, the melt mixing process is preferred. It is more complex but very effectively combines the bond materials. The steps are as follows.
EXAMPLE 1
Binder Mix
Epoxy chips are reduced to less than 60 mesh by a hammer mill, although a pin wheel type mill may be used. The resultant epoxy powder is batch mixed with the powdered curing agent and accelerator, as follows:
Weight
100 lbs D.E.R. 642U molecular weight 560 epoxy resin (Bis A Type) binder by Dow Chemical
5 lbs Amicure CG-1200 dicyandiamide curing agent by Pacific Anchor
2 lbs Omnicure 24 immidizole accelerator by Omicron
The three powders are batch mixed in a ribbon blender. A cone blender, or high intensity mixer may be used for the batch mixing. The mixed powders are then fed into a melt mixer, an extruder, in which the powders are heated to the softening point of the epoxy. While heat is being applied, a mixing screw kneads the softened powders, forcing them into close and uniform distribution. The screw continues this kneading action as it transports the hot, doughy mix through the screw mixing chamber toward the discharge section.
At the discharge end of the mixer, the mix is forced into a ribbon shape by a die and it is discharged and then chilled by passing it through a set of two chilled rolls. The rotating rolls cool the ribbon mix sufficiently, and it is broken into thin chips by a granulator. The chips of the epoxy mix are then pulverized by a hammer pulverizer into powder. Due to the heat sensitivity of this material and the small particle size required, a hammer mill is preferred but a pin-wheel type pulverizer may be used. The chips may be cooled by liquid nitrogen while being pulverized in order to increase the speed of the material through the pulverizer, the thruput, and insure powder fineness.
Grinding wheel formulas vary greatly depending on the requirements of the job to be done, but all the inventive formulas include the low molecular weight epoxy resin same and distinguishes this invention from conventional grinding wheel formulations. A particular formula involves the selection of an abrasive material, a bond material, a filler material, if any, and a wetting agent. In addition, the proportions of these ingredients vary according to the purpose of the wheel. In-house and field tests have shown that the following formula proves very successful when used for centerless grinding of stainless steel bars. The wheel size is 20 inches outside diameter×6 inches thick×12 inches inside diameter and it weighs 81.81 lbs after being trimmed.
EXAMPLE 2
Grinding Wheel
______________________________________ Weight______________________________________silicon carbide abrasive 82.76 partsgrainsD.E.R. 642U epoxy resin binding 16.11 partsmaterial by Dow ChemicalAmicure CG-1200 dicyandiamide .81 partscuring agent by Pacific AnchorOmicure 24 immidizole accelerator .32 partsby Omicron Chemicals, Inc.,Hackettstown, NJ 100.00wetting agent = 1% of grain 8.28weight______________________________________
EXAMPLE 3
Grinding Wheel
______________________________________ Weight______________________________________silicon carbide abrasive 70.50 lbs.grainsD.E.R. 642U epoxy resin binding 13.73 lbs.material by Dow ChemicalAmicure CG-1200 dicyandiamide .69 lbs.curing agent by Pacific AnchorOmicure 24 immidizole accelerator .27 lbs.by Omicron Chemicals, Inc.,Hackettstown, NJUnion Carbide Organofunctional 238 gramsSilane A 1873/4% of the siliconcarbideNeutral Oil, C-4 Neutral Oil 79 gramsX-2 by Coopers Creek ChemicalCorp., West Conshohocken, PA1/4% of the Silicon Carbide______________________________________
The abrasive grain is coated with the wetting agent and then mixed with the powdered bond materials, the epoxy resin, curing agent, and accelerator. The wheel mix is then weighed, poured into a steel mold, leveled and then compacted in a hydraulic press to form a "green" wheel. Pressure necessary to compress the mix to the specified thickness is in the range of 1.5 tons per square inch of the top surface area of the wheel as it sits in the mold. The above wheel requires 300 tons of pressure. The green wheel is stripped from the mold and placed in an oven.
The wheel is cured in the oven and the oven cure cycle runs 23 hours and the temperature of the oven is about 350 degrees F.
By comparison, a cure cycle for phenolic wheels of this size runs from 48 to 66 hours and the temperature of the oven is 370 degrees F. A cure cycle for vitrified wheels of this size runs from 96 to 120 hours and reaches 2300 degrees F.
After the grinding wheel is cured, it is removed from the oven and cooled to room temperature.
Results of tests involving the above wheel as used on a centerless grinding machine and grinding 3/8 inch diameter.×12 foot long bars of type 303 stainless steel are:
thrufeed of bar--48 feet per minute
stock removal of bar--0.005 inches
wheel loss per bar--0.0004 inches
The thrufeed rate was extremely high compared to what is commonly experienced with conventional wheels. At a removal rate of 0.005 inch per bar, common practice is to set the thrufeed of the bar at 12 feet or at most, 24 feet. Above that, a wheel usually breaks down or wears at an excessive rate. The innovative wheel, however, maintains its integrity better by keeping the individual abrasive grains from being pulled from the wheel matrix prematurely. This could be attributed to the higher tensile strength and higher heat resistance of the lower molecular weight epoxy bond compared to the traditional phenolic bond commonly used for this type application.
A comparison of typical resin properties is as follows:
______________________________________ Inventive Conventional EPOXY (novolac) PHENOLIC______________________________________tensile strength, 14 max 7.5 max1000 psielongation, in 2 in., % 2-5 neglig.hardness, Rockwell M90-110 M105-120impact strength, Izod, 0.2-1.5 0.2-0.6ft-lbflexural strength, 8-20 7-121000 psiheat distortion temp, F. 500 300-350______________________________________
ADVANTAGES
This construction combines the manufacturing efficiencies of the dry phenolic resin process with the superior physical properties of the liquid epoxy resin process. It also has another advantage, that of minimal environmental impact--unlike either the traditional dry phenolic or the liquid epoxy resin processes which may emit hazardous gases or must be cleaned by hazardous solvents.
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Grinding wheels are constructed with an improved type of resin binder of a low molecular weight solid epoxy resin. The epoxy resin is in the form of a fine powder and may be mixed with other wheel components such as abrasive grain, wetting agent and fillers. A method in which the epoxy resin and curing agents are processed from their commercially available forms to that most suitable for use as a grinding wheel binder.
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BACKGROUND OF THE INVENTION
The present invention relates to a broad beam ultrasonic transducer.
U.S. Pat. No. 4,677,377 discloses a piezoelectric transducer which is intended to be used as an emitting transducer or as a receiving transducer for ultrasonic waves propagating in air. The use of the transducer disclosed by this publication has solved substantial problems which are associated with the extreme difference between the acoustic wave impedance of the sound-transmitting medium of air and the acoustic wave impedance of a solid body emitting or receiving the ultrasonic waves. This acoustic wave impedance is also referred to as the acoustic characteristic impedance.
The ultrasonic transducer of the aforementioned publication has an acoustic characteristic impedance which in relative terms is substantially closer to the value thereof of air. This is achieved by a sandwich construction which consists of individual mutually spaced piezoelectric laminae disposed in planes parallel to one another, the intermediate spaces, corresponding to the spacings, between these laminae being filled with an inherently stable material which has a low acoustic characteristic impedance value. The material occupying the intermediate spaces forms at least one closed surface of this electroacoustic transducer enclosing the piezoelectric laminae, namely a surface for the emission and/or for the reception of acoustic radiation. In this case, for example, this material occupying the intermediate spaces may extend beyond at least a respective one of the edge surfaces of the individual laminae, so that these edge surfaces of the laminae are covered in relation to the external environment by this material occupying the intermediate spaces.
Such a known transducer may be designed so that this surface of the same which is provided for emission and/or reception has relatively large dimensions as compared with the wavelength, in air, of the emitted or received acoustic radiation. If the individual piezoelectric laminae are excited to execute co-phase oscillation, then, originating from this surface of the transducer, an acoustic wave with a substantially plane phase front is emitted.
The material employed for the laminae is piezoelectric ceramic, e.g. lead zirconate titanate, lead titanate, barium titanate and the like, it being possible for these materials to include dopings and/or substitutions, of, inter alia, manganese, niobium, neodymium etc. to improve their respective properties. The material intended to occupy the intermediate spaces between the laminae is, in this known transducer, for example a thermoplastic material. By way of example, the entire body consisting of this material and the piezoelectric laminae is adhesively bonded together while hot. However, the intermediate spaces in this body may also be filled with a sealing compound consisting of silicon rubber.
With regard to further details with respect to the structural configuration and the production of such a known transducer, reference is made to the aforementioned publication.
SUMMARY OF THE INVENTION
The object of the present invention is to provide an electroacoustic transducer with favorable matching of the acoustic characteristic impedance to the medium of air, which transducer has as its acoustic radiation lobe one which has a relatively small width in the x coordinate direction perpendicular to the direction z of the axis of the acoustic radiation, i.e. a small beam width, and which has a broad beam in the coordinate direction y which is respectively perpendicular to this direction x and to the axial direction z, i.e. possesses a broad beam width in this direction. The structural configuration of the transducer to be provided is intended to be such that, proceeding from a basic type, individual types with beam widths in the y direction which differ from one another in a predeterminable manner can be obtained by the selection of individual dimensions. In particular, it is intended that the broad beam width can be selectable within the range from 50° to 100° (-6 dB) for the individual type of transducer.
This object is achieved with a transducer having a transducer body in the form of a parallelepiped with the length (L), the width (B) and the thickness (D) and one surface of the transducer body as a sound-emitting and/or sound-receiving surface (5). The transducer body has on one hand at least one lamina provided with electrodes and which consists of piezoelectric material and, on the other hand, at least two plates/films consisting of a plastic material. These laminae and plate/films are alternately connected to one another in succession in the direction of the thickness of the parallelepiped. The ratio of the width to the length of the parallelepiped is at least approximately 0.42. The long lateral surface (thickness×length) of the parallelepiped is the sound-emitting and/or sound-receiving surface. The plastic material is a material having a mechanical oscillation quality factor in the order of magnitude of that of the piezoelectric material of the laminae. This plastic material has a lower acoustic characteristic impedance than that of the piezoelectric material of the laminae, and the Poisson ratio of the plastic material is less than 0.3.
In the transducer the thickness ratio d p :d k , with d p for the components of the plates/films consisting of the plastic material and with d k for the components of the lamina consisting of the piezoelectric material, is selected so that the particle velocity of the transducer is at least approximately half as great as that of the piezoelectric material under the same excitation conditions, preferably equal voltage, in the case of resonance. The particle velocity is the velocity with which the particles (for example, air molecules) move back and forth. The plastic material of the plates/films can be a formed glass or a coarse-pored sintered glass. The sound-emitting or sound-receiving surface of the transducer body can be a closed film region consisting of the plastic material.
Highly directional transducers including, for example, the transducers disclosed in references DE-A-2,537,788 and GB-A-1,530,347, have an beam width of 5° to 10° (-6 dB). A transducer according to the invention having a beam width of, for example, 70° in the direction designated above by y and with a highly directional effect in the x direction is an extremely broad beam ultrasonic transducer. In a plane which is respectively perpendicular to the axial direction z, the cross section of the acoustic lobe of such a transducer according to the invention is relatively flat in the x direction, but on the other hand wide in the y direction, and represents, overall, a surface which, at least to an approximation, is similar to an ellipse. With increasing spacing (z-z 0 ) from the surface Zo of the transducer, this cross sectional surface area becomes progressively greater, but without losing its characteristic form of a transducer having a broad beam in a lateral direction y.
In order to achieve the object specified above, an attempt had been made to develop further the transducer disclosed in U.S. Pat. No. 4,677,337. However, it became evident that the specific object of the present invention could not be achieved in this manner. Difficulties arose, for example, if the thickness of the plastic occupying the intermediate spaces is substantially greater than the thickness of the piezoelectric laminae. In pulsed operation, the excitation of the laminae no longer led to co-phase surface deformation, on account of the low acoustic wave velocity in the y direction, but permitted interfering surface ripple to take place. In the case of resonant excitation of a pulsed transducer with the natural oscillation which is necessarily associated therewith, the gain in efficiency proved to be relatively limited. In a design and dimensions based on the object of high achieving mechanical losses, i.e. a low oscillation quality factor, the load capacity of the transducer was relatively severely limited on account of the generation of heat. The use of the above-mentioned silicon rubber or of a material comparable thereto, such materials having relatively large transverse contraction, produced excessively severe mode coupling with thickness resonances of the film transducer made using sandwich construction, specifically as soon as the stack height exceeds a specified value. In the case of pulse transducers, this is of advantage per se, since a multimode pulse transducer necessarily has a broad band. However, in the case of a single-frequency transducer, mode coupling is in most cases associated with an impairment of the electromechanical coupling factor and thus of the electroacoustic efficiency. In the case of transducers operated using a single frequency, as intended or required for the invention, a very comprehensive check of the occurrence of natural modes of the piezoelectric laminae contained in the transducer is essential with respect to the frequency, the form of the oscillation and the electromechanical coupling factor k, specifically for the purpose of achieving a defined directional characteristic and optimum efficiency. In order to achieve the object according to the invention, it would accordingly be necessary to embark upon a fundamentally new path, even though a transducer according to the invention in general again consists of rectangular piezoelectric laminae and composite material.
BRIEF DESCRIPTION OF THE DRAWINGS
The features of the present invention which are believed to be novel, are set forth with particularity in the appended claims. The invention, together with further objects and advantages, may best be understood by reference to the following description taken in conjunction with the accompanying drawings, in the several Figures in which like reference numerals identify like elements, and in which:
FIG. 1 shows the principle of a transducer according to the invention.
FIGS. 2 and 3 show specific embodiments,
FIG. 4 shows an embodiment with a plastic material covering the entire surface.
DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 shows the principle of a transducer 1, designed according to the invention, and the relative dimensions of which are selected according to the invention. In the embodiment shown in FIG. 1, this transducer 1 consists of a piezoelectric ceramic lamina 2 provided with electrodes (not shown in the figure) and of films or plates 3, 13 consisting of a plastic material. The length of the represented rectangular composite body of the transducer 1 is designated by L. Its width is designated by B. Its overall thickness is designated by D, and this is the sum of the thickness dimensions d p of the plates 3, 13 and the thickness dimension d k of the lamina 2.
That surface of the transducer 1 which is designated by 5 is the emitting or sound-receiving surface which is provided or selected in accordance with the invention. The emission provided according to the invention is indicated by the arrows 6.
The ceramic lamina 2 and the films or plates 3, 13 are firmly connected to one another over their surfaces, as shown. In the case of thermoplastic material, the bonding agent (adhesive) may be the material of the films or plates 3, 13 itself.
A transducer according to the invention may also consist of a plurality of ceramic laminae and a corresponding number of films or plates.
For the sake of completeness, reference is made to the IEEE publication, Transactions on Sonics and Ultrasonics, Vol. SU 15 (1968) pp. 97/105, where numerous forms of resonant oscillation are indicated for a rectangular piezoelectric plate, but only for a single active plate alone.
The material of the plates 3, 13 on both sides of the piezoelectric lamina 2 is selected with regard to low acoustic characteristic impedance Z and with regard to the smallest possible Poisson ration μ less than 0.3 and with regard to the highest possible oscillation quality factor Q greater than 20. A low acoustic characteristic impedance is used to achieve the best possible matching to the sound transmission medium of air. A small Poisson ratio contributes to the avoidance, as far as possible, of the excitation of transverse modes. In fact, these may already occur in circumstances in which the thickness D is even smaller than the width B of the transducer 1. A high quality factor Q of this material permits the achievement of oscillatory deflection in the material of the plates 3, 13, which approximates to and preferably exceeds the oscillatory deflection of the ceramic lamina 2. An example of such a material is that material which is described in reference DE-C-2,537,788 and in reference GB-A-1,530,347, and which is an epoxy resin filled with glass or silicon dioxide hollow spheres, also known under the trademark Scotch-Ply. Another material is polystyrene, a "glass foam", a sintered glass or the like. Where in this instance the material of the plates/films 3, 13 . . . is designated as plastic material, the mineral substance "glass" in forms as indicated is also included within the meaning of the invention.
According to the invention, the ratio of the two dimensions B and L indicated in FIG. 1 is dimensioned as:
B:L at least approximately=0.42.
Using this specified dimensioning, according to the invention a mode of oscillation of the transducer 1 is ensured in which the surface 5 oscillates as far as possible approximately in-phase i.e. executes a "piston oscillation", and specifically with a coupling factor which is high at the same time.
FIG. 2 shows an embodiment according to the invention with two ceramic laminae 2 and with 3 plates, 3, 13, 23.
FIG. 3 shows an embodiment, likewise according to the invention, with two ceramic laminae 2, one plate 3 and two coatings 3 1 and 3 2 , which are considerably thinner as compared with the thickness of the plate 3 and which are situated on the outwardly pointing surfaces of the ceramic laminae 2.
Preferably, an embodiment according to FIG. 1 is selected if the quality factor Qp of the material of the plates 3, 13 . . . is smaller than the quality less factor Q k of the piezoceramic of the laminae 2. If Q p is approximately equal to Q k , the selection of a transducer according to FIG. 1 is recommended. If Q p is greater then Q k , an embodiment according to FIG. 3 is expediently selected, and specifically with 1/2 d p greater than d p , greater than 1/5 d p . For the purpose of the respective selection, the decisive matter is the specified objective of ensuring an amplitude decreasing towards the edge regions with an as far as possible (transversely to the laminae) in-phase oscillation behavior of the emitting surface 5; this gives rise to a directional behavior which has few sidelobes.
In the case of all embodiments, the plastic material can also cover the entire surface 5, as shown by FIG. 4 with the film region 51.
Optimum acoustic effectiveness for a mode of oscillation arises for a transducer according to the invention if the thickness ratio d p :d k is selected to be optimum. Other modes which have an interfering effect are avoided by complying to the above specification, namely that the plastic material is so selected or is present in such a form (e.g. foam) that its Poisson ratio is less than 0.3. An optimum d p :d k ratio is applicable if the transducer thus dimensioned has, in the case of resonant excitation, an amplitude of oscillation or particle velocity which is half as great as is applicable in the case of a transducer (having the same external dimensions) which however consists purely of the piezoelectric material or is not such a composite transducer. In these circumstances, the oscillation energy is apportioned by halves to the two material components of the individual transducer.
The invention is not limited to the particular details of the apparatus depicted and other modifications and applications are comtemplated. Certain other changes may be made in the above described apparatus without departing from the true spirit and scope of the invention herein involved. It is intended, therefore, that the subject matter in the above depiction shall be interpreted as illustrative and not in a limiting sense.
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Disclosed is a broad beam ultrasonic transducer of sandwich construction, having piezoceramic laminae (2), fitted with electrodes, and plates/films (3, 13) in the shape of a parallelepiped with a width (B) to length (L) ratio of 0.42 and in which the relative thicknesses of the piezoceramic laminae and the plates/films are chosen such that one side surface of the parallelepiped undergoes an in-phase oscillation behavior.
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REFERENCES SITED:
[0001] U.S. Patent Documents
[0002] U.S. Pat. No. 2,630,777 Johnson
[0003] U.S. Pat. No. 2,964,010 Harrison
[0004] U.S. Pat. No. 5,311,835 Knowles
[0005] U.S. Pat. No. 5,462,006 Thiruppathi
[0006] U.S. Pat. No. 5,515,809 Weinberg
[0007] U.S. Pat. No. 5,819,451 Khon
[0008] U.S. Pat. No. 7,260,025 Farinella et al
[0009] USD560720 Madden et al
[0010] USD313627 Diaz
[0011] USD534584 Goldberg et al
[0012] US20050242567 Palamidessi
FIELD OF INVENTION
[0013] Convention bookmarks are used to mark or identify two pages of text. They can also be used to identify the location of a particular section of text on a page. And while the bookmark themselves can have different graphic images and text printed on their surface. Those images like the text are stagnant and non-moving.
BRIEF SUMMARY OF THE INVENTION
[0014] It is an object of the present invention to provide a flexible electronic bookmark which will allow for the display of moving text and images on its surface. This is achieved by the flexible electronic bookmark provided by the present invention, in which a substrate of a thickness suitable for use between pages. The substrate will be composed of a thin electronic display or some other media suitable for the display of moving text and images on its surface, and appropriate circuitry. The thin electronic display or media should be flexible in nature so that it will not be damaged as the flexible electronic bookmark bends. A flexible material completes the backing of the flexible electronic bookmark and protects the control circuitry. At one end of the bookmark is a male plug.
BRIEF DESCRIPTION OF DRAWINGS
[0015] In this preferred embodiment:
[0016] FIG. 1 is a perspective view of the flexible electronic bookmark
[0017] FIG. 1 a is a perspective view of the flexible substrate backing
[0018] FIG. 1 b is a perspective view of the flexible electronic circuit board
[0019] FIG. 1 c is a perspective view of the flexible electronic display unit
[0020] FIG. 2 is a frontal view of the flexible electronic bookmark
[0021] FIG. 3 is a rear view of the flexible electronic bookmark.
[0022] FIG. 4 is a top view of the flexible electronic bookmark
[0023] FIG. 5 is a bottom view of the flexible electronic bookmark
[0024] FIG. 6 is a right side view of the flexible electronic bookmark; the left side view of the flexible electronic bookmark is a mirror image of the right side.
[0025] FIG. 7 is a rear view of the flexible electronic bookmark with break away cover section
DETAILED DESCRIPTION OF INVENTION
[0026] In the preferred embodiment as described in FIG. 1 the flexible electronic bookmark ( 1 ) is comprised of a thin flexible electronic display unit ( 2 ) with appropriate flexible electronic circuit board ( 3 ) used for controlling the display of text and images and regulating voltage and a substrate backing ( 4 ). These components are combined using an appropriate method to form one single flexible electronic bookmark ( 1 ) as pictured in FIGS. 1 through 6 As demonstrated in FIG. 1 b , the flexible electronic circuit board ( 3 ) is thin enough to remain flexible yet house the necessary circuitry to control the display of images and text on the flexible electronic display unit ( 2 ) of FIG. 1 c . In the preferred embodiment the flexible electronic display unit ( 2 ) is comprised of a thin-film polymer or other flexible substrate capable of displaying moving text and images. This flexible substrate or polymer is attached to the flexible electronic circuit board ( 3 ) which is comprised of printed electronics or some other means of electronic fabrication, which then controls the display of text and images on the flexible electronic display unit ( 2 ). The flexible electronic display unit ( 2 ) is attached to the flexible electronic circuit board ( 3 ) by some appropriate means. The flexible electronic bookmark ( 1 ) also has at one end a notched male plug ( 5 ) which is used to plug the bookmark into an appropriate device for programming text or images into the bookmark's memory unit housed on the flexible electronic circuit board ( 3 ).
[0027] As demonstrated in FIG. 3 and 1 a , the flexible substrate backing ( 4 ) is used to provide additional stability and protection to the flexible electronic bookmark ( 1 ).
[0028] This represents the preferred embodiment however those skilled in the art will appreciate that various adaptations and modifications of the just-described preferred embodiment can be configured without departing from the scope and spirit of the invention. Therefore, it is to be understood that within the scope of the appended claims the invention may be practiced other than as specifically described herein.
[0029] Another modification of the flexible electronic bookmark ( 1 ) as pictured in FIG. 7 the flexible substrate backing ( 4 ) has a break away cover ( 6 ) that can house a battery power unit connected to the flexible electronic circuit board ( 3 ) by some means. Said battery power unit being thin enough to properly fit into a cavity provided by the removal of break away cover ( 6 ).
[0030] In another modification is to include a RFID device capable of receiving information for display on the flexible electronic bookmark ( 1 ) from another source such a wireless router or some other device capable of streaming information wirelessly to a receiving device.
[0031] In another modification of the device the flexible substrate backing ( 4 ) can be composed of a flexible solar cell material capable of recharging the battery for the flexible electronic bookmark ( 1 )
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The present invention relates to a flexible bookmark and more particularly a bookmark capable of displaying active text and images on its surface.
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This is a continuation of application Ser. No. 08/059,893, filed May 10, 1993 now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to improvements in user interface control devices for personal computers and, more particularly, pertains to new and improved yoke construction wherein complete aileron, elevator, and throttle control, among other controls, are provided to the user.
2. Description of Related Art
In the field of user interface devices for game applications, it has been a practice to employ joystick devices for the user to manipulate as the input device for a flight control computer game or driving game. Such devices have fallen short in providing the user with adequate control and a feeling of reality. To provide the user with a more realistic feeling of controlling an aircraft, some prior art devices have configured a joystick to appear more like a control stick in an airplane. Other devices have adapted and used a steering wheel-type configuration for aircraft and automobile games. All such devices have been unsatisfactory in that they still do not provide for a real sense of control and maneuverability to the user of such interface devices for flight control computer games or automobile driving games.
The present invention provides the user with a more realistic feel of movement of the interface device and more accurate control of the computer game.
SUMMARY OF THE INVENTION
A control housing containing electrical components is securely fastened to a support surface by a pair of pivoting clamp mechanisms. A control wheel containing electrical components is rotatably attached to a control wheel column. Rotation of the control wheel, left or right, with respect to the control wheel column, actuates an aileron control electrical component mounted inside the control wheel. The control wheel column is movably attached to the control housing. Moving the control wheel column into and out of the control housing actuates an elevator control electrical component mounted in said control housing.
BRIEF DESCRIPTION OF THE DRAWINGS
The exact nature of this invention, as well as its objects and advantages, will become readily apparent upon reference to the following detailed description when considered in conjunction with the accompanying drawings, in which like reference numerals designate like parts throughout the figures thereof, and wherein:
FIG. 1 is a perspective illustration of the present invention used in connection with a personal computer;
FIG. 2 an end elevation of the present invention;
FIG. 3 is a bottom view of the present invention;
FIG. 4 is a side view cross-section of the control housing for the present invention showing the components therein;
FIG. 5 is a top view cross-section of the control housing of the present invention;
FIG. 6 is a cross-section taken along lines 6--6 of FIG. 5;
FIG. 7 is a cross-section taken along lines 7--7 of FIG. 5;
FIG. 8 is a side elevation of just the elevator trim tab of the present invention;
FIG. 9 is a side elevation of just the elevator trim tab of the present invention;
FIG. 10 is a bottom view in partial showing one of the elements of FIG. 5;
FIG. 11 is a bottom view in partial showing the same elements shown in FIG. 10, in a different position;
FIG. 12 is a front view of the control wheel with its top cover removed;
FIG. 13 is a cross-section taken along line 13--13 in FIG. 12;
FIG. 14 is a top, partially broken-away view of the top of the control wheel of the present invention;
FIG. 15 is a cross-section taken along lines 15--15 of FIG. 13 showing the inner workings of part of the mechanism located in the control wheel;
FIG. 16 is a cross-section taken along lines 15--15 of FIG. 13 showing the inner workings of part of the mechanism located in the control wheel when rotated in direction 175 (counter-clockwise in relation to the operator; and
FIG. 17 is a cross-section taken along lines 15--15 of FIG. 13 showing the inner workings of part of the mechanism located in the control wheel when rotated in direction 177 (clockwise in relation to the operator.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following description is provided to enable any person skilled in the art to make and use the invention and sets forth the best modes contemplated by the inventor of carrying out his invention. Various modifications, however, will remain readily apparent to those skilled in the art, since the generic principles of the present invention have been defined herein specifically to provide a yoke control simulator for computer games that has the capability of complete aileron and elevator control, a throttle control, and various pushbuttons, as shown in FIG. 1.
The control simulator 11, which can be used for flight control games and automobile driving games according to the present invention, comprises a control housing 13 which is firmly clamped to table 12 by way of a desk clamp mechanism 31 which is tightened by a desk clamp knob 33. A control wheel shaft 21 is mounted within bearings 22 to move laterally in direction 19 with respect to control housing 13.
A control wheel 15 is movably mounted to the control wheel shaft 21 so as to rotate about the symmetrical axis of shaft 21 in direction 17. Thus, rotation of control wheel 15 to the left or right in direction 17 will be with respect to a nonrotating shaft 21, shaft 21 being allowed to move only in a direction 19 in and out of control housing 13.
The control housing 13, which has mechanical and electrical components therein, which will be discussed hereinafter, is connected to a computer such as a personal computer 35 by way of standard cables 51 and connector 53 (FIG. 2). The computer has a video display 37, the video display illustrating scenes 39 as directed by the game software loaded into the computer 35. The scenes 39 may be landscape scenes over which the imagined airplane, controlled by control simulator 11, is flying.
Control housing 13 has controls thereon, such as elevator trim tab 25 and throttle control 23. Control wheel 15 contains an aileron trim tab 36 and a pair of buttons 27, 29 which may be a gun, fire buttons, or used for some similar function, for example.
As shown in FIGS. 2 and 3, the control wheel shaft 21 extends through the upper part of control housing 13, coming out the back end of housing 13, and sliding within bearings 22 and 49. FIG. 2 illustrates the cable 51 and connector 53 which plugs into computer 35 (FIG. 1).
Control housing 13 is constructed so that its front side 24 (FIG. 1) is wider than its back side 26. When in place for use, the front side 24 hangs over the edge of a mounting surface 12 with the narrower part of control housing 13 resting on support surface 12. The depth of the front part 24 is small so that almost the entire length 54 of the control housing rests on support surface 12.
Located partially within the front section of control housing 13 is a pair of mounting clamps 31, 41 mounted at the respective sides of control housing 13. The desk clamps 31 and 41 are mounted within the larger front end 24 of housing 13 to pivot around their respective inside ends so that the outside ends 46 of clamp 41, and 48 of clamp 31, move up and down with respect to undersurface 54 as the respective mounting knobs 43 and 33 are tightened. Mounting clamp 41 rides on a bushing 45. Mounting clamp 31 rides on a bushing 47. The bushings allow for free rotation of mounting knobs 43 and 33, respectively. Mounting knobs 43 and 33 are fixedly attached to threaded shafts 42 and 32, respectively, which are journalled through portion 44 and 34, respectively, of support structures located within the upper portion of control housing 13 to threadably engage these respective support structures, as will be more clearly described hereinafter.
FIG. 4 is a side view cutaway section of the control housing of FIG. 1. The support structure 69 located within the larger front portion 24 of control housing 13 is L-shaped with an elongated section 71 extending towards the back end 26 of control housing 13. The other leg 69 of L-shaped member 73 extends down towards the pivot points 63 of clamp 31. Shaft 32, which is fixedly attached to mounting knob 33, is journalled through this part 69 of support member 73 to threadably engage nut 75, which is fixedly contained within support member 73.
As mounting knob 33 is rotated, causing shaft 32 to be threaded into nut 75, clamp 31 pivots about pivot studs 63, causing its other end 48 to move upward in the direction 67 until the contact round 65 on clamp 31 connects the underside of support surface 12, rigidly holding the entire control housing 13 to surface 12. Support structure 73, through its extended length 71 and its shorter length 69, absorbs the holding forces exerted whereby the support surface 12 is squeezed between support structure 73 and clamp 31 without any adverse effects on the shell of control housing 13. This structure allows support member 73, through its elongated end 71 and its shorter end 69, to absorb all the forces, rather than the skin 54 of control housing 13.
To loosen the holding mechanism, mounting knob 33 is rotating in the opposite direction, causing threaded shaft 32 to back out of nut 75, thereby allowing clamp 31 to pivot around pivot studs 63 in a downward direction 67. Clamp 31 has a truncated prism-shaped aperture 34 there-through, allowing clamp 31 to pivot in direction 67 about shaft 32. This structure accommodates a variety of thicknesses of support surfaces 12 and permits a very secure holding mechanism which is unobtrusively located within and integral to the control housing 13.
The control wheel shaft 21 slides within a pair of bushings, bushing 22, located at the front face 24, and bushing 49, located at the rear face 26 of control housing 13. Control wheel 15, in turn, is mounted for rotation about shaft 21 with a bearing surface 56 (FIG. 3) located on the inside of boss 55, which will be more fully described hereinafter.
A throttle control lever 23 is mounted for rotation with the control shaft of a variable resistor 61. Moving throttle 23, back 59 and forward 57, changes the setting of variable resistor 61, which commensurably changes the simulated speed of flight compatible with the program being used.
Referring now to FIGS. 5 and 6, the elevator control mechanism of the present invention will be explained. Control wheel shaft 21 slides back and forth along direction 19 within bearings 22 and 49. Shaft 21 is prevented from rotating by a boss 83 fixedly attached thereto on its top side and a boss 84 fixedly attached thereto on its bottom side (FIG. 6). Bosses 83 and 84 ride within respective tracks 105 and 101. A pair of pivoting arms 81 and 103 are mounted to variable resistor 95 for pivotal movement with the rotation of the shaft of variable resistor 95.
Each pivoting arm 81 and 101 has an elongated slot therein, such as slot 85 located in pivoting arm 81. Movement of shaft 21 in a direction 19 causes pivoting arms 81 and 103 to pivot back and forth about the symmetrical center of variable resistor 95 with its control shaft. Back-and-forth movement 19 of the control wheel shaft 21 is the elevator control for the simulated airplane in the computer game, causing the airplane to dive or climb in response to shaft 21 being pushed towards the control housing 13 or pulled away from the control housing 13.
The movement of control wheel shaft 21 back and forth in direction 19 causes control arms 81 and 103 to move back and forth in direction 79 against a spring 93, which is connected to a pair of scissor legs 89 and 91. As will be more fully explained hereafter, movement of the control wheel shaft 21 in the direction 19 against spring 93 gives the user a more realistic control feel during play.
The trim tab wheel 25 mounted in control housing 13 is connected to variable resistor 95 by linkage arm 97 and lever arm 99. Elevator trim wheel 25 is simply the zeroing mechanism for variable resistor 95 so that a ground level or start level may be manually adjusted before the start of a game.
The elevator trim wheel 25 is more fully illustrated in FIGS. 7, 8, and 9. Trim wheel 25 is mounted for rotation about axis 111. This rotational motion is converted into translational movement by linkage arm 97, which connects to pivoting arm 99, which is physically attached to the housing of variable resistor 95. Linkage arm 97 has a large end 110 within which is located a horizontal elongated slot 107 and a shorter, vertical elongated slot 109. The rotational pivot shaft 111 of elevator trim wheel 25 is located within horizontal slot 107. Smaller boss 113 is located within vertical slot 109. Boss 113 is directly beneath pivot shaft 111.
With the linkage arm 97 and the elevator trim wheel 25 in the position indicated in FIG. 7, the variable resistor 95 is positioned with respect to its rotating shaft 106 to be approximately in the center of movement or travel for rotating shaft 106. The entire assembly, including the upper arm linkage 81 and the lower arm linkage 103, the scissor mechanism 91, the variable resistor body 95, and link arm 99, which is connected to the body of resistor 95, are held from movement vertically and horizontally by the top skin 84 and the bottom skin 104 of control housing 13.
Referring now to FIG. 8, movement of the elevator trim wheel 25 in an upward direction 115 causes linkage arm 97 to move away from variable resistor 95 in direction 117, which causes the body of variable resistor 95 to rotate in a counterclockwise direction 119. Rotatable shaft 106 is held stationary by lever arm 103 in a manner which will be more fully explained hereinafter. As can be seen in FIG. 8, the pivot shaft 111 of elevator trim wheel 25 and boss 113 of elevator trim wheel 25 have moved to the extreme left position of slot 107 and the extreme upper position in slot 109, respectively.
Referring now to FIG. 9, if elevator trim wheel 25 is moved in a downward direction 125, linkage arm 97 is moved towards the variable resistor 95 in direction 123, causing linkage 99, which is connected to the body of resistor 95, to rotate in a clockwise direction 121 with respect to the shaft 106 of resistor 95. As can be seen in FIG. 9, the pivot shaft 111 of elevator trim wheel 125 is moved to the extreme right position in slot 107, while boss 113 is moved through a complete cycle in slot 109 from the top to the bottom and back to the extreme top position again.
Once the elevator trim wheel 25 is adjusted for the reference or ground plane position for the particular computer game being utilized, elevator trim wheel 25 is no longer used.
During game play, the shaft 106 of variable resistor 95 is varied to create the elevator control signals, depending upon movement of the control wheel shaft 21 in and out of control housing 113, as can be more clearly seen in FIGS. 10 and 11. The bottom lever arm 103, having a slot 129 at one end thereof, is connected to shaft 21 by boss 84. Boss 84, as will be remembered, is fixedly attached to shaft 21 so that movement of shaft 21 in a direction 127 or 133 will cause boss 84 to move as well. The other end of linkage arm 103 is fixedly attached to the movable shaft 106 of variable resistor 95, the linkage arm 103 essentially pivoting around the rotational center of variable resistor shaft 106.
The scissor mechanism, which is more clearly visible from the bottom in FIGS. 10 and 11, can now be seen to have two arms, 89 and 91, which also rotates about the symmetrical center of shaft 106 of variable resistor 95. In a neutral position (FIG. 5) with the spring not expanded, lever arm 103 is in a position perpendicular to shaft 21. Stub 136, which is physically attached to support plate 87, and stub 131, which is physically attached to the upper surface (far side in FIG. 10 and 11 of linkage arm 103, are located essentially next to each other, along the axis of lever arm 103 when in the neutral position, with both stubs 136 and 131 touching both edges 134 and 132 of scissor arms 89 and 91, respectively.
Because the view of FIG. 10 is from the bottom, movement of shaft 21 in direction 127 is a movement of control wheel 15, attached to control wheel shaft 21, away from control housing 13. Such movement causes boss 84, within slot 129 of linkage arm 103, to move that end of linkage arm 103, causing the other end to pivot shaft 106 of the variable resistor.
This pivoting motion, as a result of stub 131 abutting edge 132 of scissor arm 91, is against spring 93, causing it to expand as illustrated. As a result, if the operator releases the control wheel 15, control wheel shaft 21, due to the forces of expanded spring 93 tending to contract, will bring linkage arm 103 back to its original rest position.
When control wheel 15 is moved in the opposite direction 133, shaft 106 of variable resistor 95 is rotated in the opposite direction as well. This time the movement of linkage arm 103 is against contact surface 134 of scissor arm 89, causing spring 93 to expand as shown in FIG. 11. When the control wheel 15 is released, shaft 21 will move back to its home position due to the force of spring 93 moving linkage arm 103 back to its neutral home position.
Thus, the operator having elevator control of the simulated airplane of the computer game can pull the steering wheel out to cause the airplane to apparently climb and push the steering wheel in to cause the airplane to dive. Simply leaving the steering wheel stationary will cause the airplane to stay at its reference level as set by the elevator trim wheel 25. The result is that a realistic feel is provided to the operator when controlling the airplane to dive and climb.
To control the ailerons of the simulated airplane to cause the airplane to bank left and right, the operator turns control wheel 15 in a counterclockwise or clockwise direction 169, as shown in FIG. 14. This causes the shaft 152 of variable resistor 151 to rotate. As will be more fully explained hereinafter in connection with FIGS. 12 and 13, movement of wheel 15 in direction 169 causes a linkage arm 145 to move the variable shaft of resistor 151 by pivoting about the rotating central axis of that shaft. Linkage arm 145 has a slot 147 located therein within which a stud 149 is located. The stud is attached to a disk 153 (FIG. 12) that is physically attached to the control wheel column 21. It will be remembered that control wheel column 21 does not rotate, but is limited to linear movement in and out of control housing 13. Thus, rotation of control wheel 15 is with respect to a stationary stud 149, which causes the respective movement of linkage arm 145 to 145' and back as illustrated in FIG. 14. Aileron trim lever 36 is located in the face of control wheel 15 and adjusts the neutral position for the aileron controls by way of linkage arm 143 in a manner that will be described hereinafter in connection with FIGS. 12 and 13.
Referring now to FIGS. 12 and 13, the moving electrical parts located within control wheel housing 15 are illustrated. FIG. 12 shows all the parts therein with the cover removed. FIG. 13 is a cross-section taken along lines 13--13 of FIG. 12, showing the interrelationship of the parts in the control wheel housing 15.
Control wheel housing 15 contains within it a potentiometer 151 which provides the signals to the computer for effective aileron control, i.e., left and right turns, for the simulated aircraft. As was already described, a disk 153 mounted under a cover 155 has a stud 149 attached thereto. Lever arm 145, which has an elongated aperture 147 at one end thereof, engages and encompasses stud 149 within the elongated aperture. The other end of linkage arm 145 is connected to rotational shaft 152 (FIG. 13) of potentiometer 151. Thus, movement of rotational arm 145 causes shaft 152 of potentiometer 151 to rotate in a clockwise or counterclockwise direction. Linkage arm 145 is caused to rotate by the user turning the control wheel 15 in a clockwise or counterclockwise direction 169 (FIG. 14).
Linkage arm 135 has, at one end thereof, an upstanding knurled portion 36, and at the other end an elongated aperture 139 that engages an upstanding stud 141 which is physically attached to a second linkage arm 143. Knurled portion 36 is an aileron trim tab which adjusts the neutral or start position for the simulated aircraft so that when the control wheel 15 is in a straight-ahead location as shown in FIG. 12, the signal provided by the variable resistor to the computer so indicates. Lever arm 135 pivots about a stationary stud pivot 137 so that movement of the upstanding knurled portion in a direction 138 to position 135', for example, causes the other slotted end of lever arm 135 to move in the opposite direction, as shown by the dotted lines. Second lever arm 143 is connected to the body of variable resistor 151 (FIG. 13) so that movement of lever 143 rotates the body of resistor 151 with respect to its shaft 152. The shaft of resistor 151 is held stationary by lever arm 145 unless control wheel 15 is rotated, as will be more fully explained hereinafter. Once the aileron trim tab 36 has been adjusted, it is left alone and it is not utilized during the remainder of game play.
Game play proceeds with the operator turning control wheel 15 clockwise or counterclockwise and pushing buttons 27 or 29 to fire weapons or the like. When control wheel 15 is turned clockwise or counterclockwise, it is turned against the force of the spring 167 which is attached to a scissor mechanism having a pair of spring-loaded arms 165, 171 (FIGS. 15, 16, and 17) and a pair of actuated arms 161, 173. Arms 171 and 161 are connected to a sleeve bearing 163, which rotates about control wheel column 21. Arms 165 and 173 are attached to the sleeve bearing 164, which is located below sleeve bearing 163 and also rotates about control wheel column 21. The inside of control wheel column 21 has a pair of key slots 168 therein which receive the key on disk 153 (FIGS. 12 and 13) so that disk 153 is fixedly attached to the end of control column 21 so that disk 153, like control column 21, is prevented from rotating. Disk 153 has attached thereto, on its rear surface, a rectangular stud 157 which extends to the rear and between the pair of control arms 161 and 173 (see also FIG. 13). The back side of the control wheel 15 has fixedly attached thereto a rectangular stud 159, which extends forward between the pair of control arms 161 and 173 of the scissor mechanism. FIG. 15 indicates the position of the two rectangular studs 157 and 159 with respect to the scissor arms 161 and 173 when the control wheel 15 is steering straight ahead.
If the control wheel 15 is turned in a clockwise direction 175 (as needed in FIG. 16), the control wheel 15 turns with respect to and around control shaft 21, causing rectangular stud 159 to move control leg 161 of the scissor mechanism away from control leg 173 against the force of spring 167. If control wheel 15 is released by the operator, the force of spring 167 and its tendency to return to its neutral state will cause control arm 171 to move rectangular stud 159 back to the position of stud 157, thereby rotating the entire wheel back to its home position.
Assuming now that control wheel 15 is rotated in a counterclockwise direction 177 (as viewed in FIG. 17), the rectangular stud 159 now moves control arm 173 away from control arm 161. In each instance when the control wheel 15 is turned, rectangular stud 157, which is located on the fixed disk 153, maintains the other control arm stationary and prevents it from following, thus causing spring 167 to expand as the control wheel 15 is turned against the force of spring 167. Once again, if the control wheel 15 is released, the tendency of spring 167 to return to its unexpanded state will cause the wheel to rotate back so that rectangular studs 159 and 157 are again aligned as shown in FIG. 15.
The result of this mechanism in the steering column is that a realistic feel is provided to the user when controlling the left and right turns of the simulated airplane. The action of the control wheel to return to a straight-ahead position simulates the action of a control wheel that is actually controlling the aileron surfaces of an airplane.
Those skilled in the art will appreciate that various adaptations and modifications of the just-described preferred embodiment can be configured without departing from the scope and spirit of the invention. Therefore, it is to be understood that, within the scope of the appended claims, the invention may be practiced other than as specifically described herein.
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A control wheel attached to a control wheel column is movably mounted to a control housing that is securely fastened to a support surface by way of a pair of pivoting clamp mechanisms. In-and-out movement of the control wheel column with respect to the control housing manipulates the elevator control mounted in the housing. Turning of the control wheel with respect to the control wheel column manipulates the aileron control mounted in the control housing. Additional button control and variable controls are mounted on the control wheel and control housing. Besides an aileron trim tab, the control wheel contains several buttons that may be used as weapons triggers. Besides an elevator trim tab, the control housing contains a throttle control.
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[0001] This application is a continuation of U.S. patent application Ser. No. 11/501,446, filed Aug. 9, 2006, the disclosure of which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] The use of RFID tags has become prevalent, especially in the management of assets, particularly those applications associated with inventory management. For example, the use of RFID tags permits the monitoring of the production line and the movement of assets or components through the supply chain.
[0003] To further illustrate this concept, a manufacturing entity may adhere RFID tags to components as they enter the production facility. These components are then inserted into the production flow, forming sub-assemblies in combination with other components, and finally resulting in a finished product. The use of RFID tags allows the personnel within the manufacturing entity to track the movement of the specific component throughout the manufacturing process. It also allows the entity to be able to identify the specific components that comprise any particular assembly or finished product.
[0004] In addition, the use of RFID tags has also been advocated within the drug and pharmaceutical industries. In February 2004, the United States Federal and Drug Administration issued a report advocating the use of RFID tags to label and monitor drugs. This is an attempt to provide pedigree and to limit the infiltration of counterfeit prescription drugs into the market and to consumers.
[0005] Since their introduction, RFID tags have been used in many applications, such as to identify and provide information for process control in filter products. U.S. Pat. No. 5,674,381, issued to Den Dekker in 1997, discloses the use of “electronic labels” in conjunction with filtering apparatus and replaceable filter assemblies. Specifically, the patent discloses a filter having an electronic label that has a read/write memory and an associated filtering apparatus that has readout means responsive to the label. The electronic label is adapted to count and store the actual operating hours of the replaceable filter. The filtering apparatus is adapted to allow use or refusal of the filter, based on this real-time number. The patent also discloses that the electronic label can be used to store identification information about the replaceable filter.
[0006] A patent application by Baker et al, published in 2005 as U.S. Patent Application Publication No. US2005/0205658, discloses a process equipment tracking system. This system includes the use of RFID tags in conjunction with process equipment. The RFID tag is described as capable of storing “at least one trackable event”. These trackable events are enumerated as cleaning dates, and batch process dates. The publication also discloses an RFID reader that is connectable to a PC or an internet, where a process equipment database exists. This database contains multiple trackable events and can supply information useful in determining “a service life of the process equipment based on the accumulated data”. The application includes the use of this type of system with a variety of process equipment, such as valves, pumps, filters, and ultraviolet lamps.
[0007] Another patent application, filed by Jornitz et al and published in 2004 as U.S. Patent Application Publication No. 2004/0256328, discloses a device and method for monitoring the integrity of filtering installations. This publication describes the use of filters containing an onboard memory chip and communications device, in conjunction with a filter housing. The filter housing acts as a monitoring and integrity tester. That application also discloses a set of steps to be used to insure the integrity of the filtering elements used in multi-round housings. These steps include querying the memory element to verify the type of filter that is being used, its limit data, and its production release data.
[0008] Despite the improvements that have occurred through the use of RFID tags, there are additional areas that have not been satisfactorily addressed. For example, to date, RFID tags cannot be employed in environments that require or utilize radiation. This is due to the fact that the memory storage devices within the RFID tag cannot withstand radiation. When subjected to radiation, specifically gamma radiation, the contents of these memory elements are corrupted, thereby rendering them useless in this environment. However, there are a number of applications, such as, but not limited to, the drug and pharmaceutical industries, where radiation of the system is a requirement. Therefore, it would be extremely beneficial to these industries and others, to have an RFID tag which could withstand radiation without data loss or corruption.
SUMMARY OF THE INVENTION
[0009] The shortcomings of the prior art are overcome by the present invention, which describes a system and method for utilizing RFID tags in environments where radiation is used. RFID tags are secured to various components of a pharmaceutical system, thereby enabling the customer to download pertinent information about the component, such as lot number, date of manufacturer, test parameters, etc. The tags can be applied to the component immediately after manufacture and can be subjected to the sterilization process without risk of data loss or corruption. The memory device within the tag utilizes a technology that does not rely upon charge storage as its mechanism to store information.
BRIEF DESCRIPTION OF THE DRAWINGS
DETAILED DESCRIPTION OF THE INVENTION
[0010] The use of RFID tags has become more and more prevalent. However, in certain applications, their use is limited, or not possible. For example, any environment in which the tag must be subjected to radiation will corrupt or destroy the contents of the memory device within the tag. Therefore, devices that are gamma irradiated, such as pharmaceutical components, or subject to x-rays, such as devices that pass through airport security systems, currently cannot utilize RFID tags. Thus, products used in these environments must find alternative solutions. For example, in some cases, a simple barcode is affixed to the device, and a database is used to store and retrieve the pertinent information associated with that barcode. In other words, the memory element of the tag is literally removed and kept elsewhere. While this allows the data associated with the device to be saved and retrieved, it requires computer access and a remote database for storage. This solution is further complicated when the device manufacturer and the device user both want to access and update the associated information. Such an arrangement requires joint access to the database, which may be difficult or impossible due to the need for confidentiality and data protection.
[0011] A second solution involves affixing the RFID tag at a point in the process after the irradiation of the device. For example, pharmaceutical components are often subjected to gamma radiation. Application of the RFID tag after this step can bypass the memory corruption issue. However, data associated with that component which was created before the radiation step must be somehow saved and associated with the appropriate component, so that the later affixed tag contains all of the required information.
[0012] A third solution is to prohibit the use of radiation with the device. Thus, users must find an alternate approach to achieve the results sought by irradiating the device (such as sterilization). Obviously, none of these solutions is optimal.
[0013] It should be noted that although the present application describes the use of RFID tags, the invention is not so limited. The fundamental issue to be solved is a limitation of the memory device used, and is not related to the particular communication protocol. Thus, while the memory devices within RFID tags clearly are affected by radiation, so too are devices which use memory devices with other communication protocols, such as Zigbee (IEEE 802.15.4), Bluetooth (IEEE 802.15.1), WiFi (IEEE 802.11), IrDA, and others.
[0014] At the root of the problem is the inability for a traditional memory device to withstand radiation. This is a very well known problem, and affects all types of memory, including FLASH, EEPROM, DRAM and SRAM. Since each of the aforementioned memory device utilizes stored charge to represent the value of each binary bit, each is susceptible to corruption caused by radiation. In this case, the charge stored in the capacitor is either depleted or enhanced by the radiation, thereby affecting its value.
[0015] There are other memory technologies that use mechanisms other than charge storage to retain the value of a bit. For example, FRAMs, or ferro-electric RAMs, utilize molecules having a bi-stable structure to store state, wherein one of the stable molecular configurations represents a ‘1’, and the other stable configuration represents a ‘0’. Several common molecules used in FRAMs are PZT (lead-zirconate-titanate), SBT (strontium-bismuth-tantalate) and BLT (lanthanum substituted bismuth-tantalate). Each possesses a central atom in a cubic unit cell having a dipole moment. These molecules switch between these two stable states based on the application of an electric field to the molecule. Since these cells rely on electrical fields, rather than charge storage, memories utilizing this mechanism are far less susceptible to gamma and other types of radiation than traditional semiconductor memory structures. Ferro-electric devices are well known and are described in more detail in U.S. Pat. No. 3,728,694, issued to Rohrer.
[0016] Another example of a memory device that does not utilize charge as the storage mechanism is MRAM, also known as magnetoresistive or simply magnetic RAM. These memory devices utilize ferromagnetic material, often in the form of Hall sensors, to store the state of the bit. Further details are provided in U.S. Pat. No. 6,140,139. Since magnetic fields are utilized, rather than capacitive charge, these memory devices are also much less susceptible to gamma radiation.
[0017] As stated above, memory devices that do not utilize charge as the storage mechanism are less susceptible to corruption due to radiation, particularly gamma radiation, thereby making them particularly advantageous in certain applications. RFID and other remotely readable tags that must pass through x-ray machines, such as airport screening machines, or tags that are used in the pharmaceutical and drug industries, can function when assembled using these memory devices.
[0018] In one experiment, RFID tags utilizing a ferroelectric memory device, and several utilizing conventional memory technology, were subjected to repeated exposure of gamma radiation. Each was subjected to a standard 25 kGray dosage. Thereafter, each was read. All of the tags utilizing the conventional memories were unreadable, while those utilizing the ferroelectric memory devices were functional. A test pattern was then written to each of the functioning devices and they were then subjected to a second dose of radiation. The tags were then retested and the test pattern was readable in each.
[0019] Based on this, it is possible to develop a sophisticated pharmaceutical asset management system. In one embodiment, the pharmaceutical components, such as filtration devices and the like, have a remotely readable tag affixed to them, such as an RFID tag. This tag contains device specific information, such as, but not limited to device specific information (such as serial number, date of manufacture, etc.), device specifications (such as upper and lower pressure limits), and device test parameters. Customers could use this information in a variety of ways. For example, an automated instrument setup and calibration procedure can be established. By using an RFID or equivalent reader, the customer could determine calibration values, upper and lower limits, units of measure and/or the data exchange protocol.
[0020] These tags can also be used in conjunction with remote sensors, such as pressure, temperature and concentration sensors. The use of these types of sensors is described in U.S. patent applications Ser. Nos. 11/402,737, 11/402,437, and 11/402,438, the disclosure of each is hereby incorporated by reference. In this case, information obtained by the sensors can be stored in the RFID tags and read by the customer at a later time.
[0021] Finally, the ability to utilize a remotely readable asset management tag is beneficial for pharmaceutical consumables, such as filters, bags, tubes and process instruments. Currently, the pharmaceutical industry is exploring the possibility of disposable technology. In this scenario, the customer could configure their required system using at least some disposable components (such as filters, bags, hoses, etc). This allows the customer to customize their configuration as necessary and also eliminates the costly cleaning operations that must currently be performed. To improve the efficiency and predictability of using disposable components, RFID tags can be affixed to these components. Such tags allow for the wireless automated identification of components, including such information as catalog number, serial number, and date of manufacture. These tags also allow a secure automated method of transferring unit specific specification to the customer as noted above. Using the information contained within these tags, a GAMP compliant method of transferring unit specific test procedure information to an automated integrity tester can be created. The memory devices described above are beneficial in this application, since these disposable components must be irradiated to insure sterilization.
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A system and method for utilizing RFID tags in environments where radiation is used is disclosed. RFID tags are secured to various components of a pharmaceutical system, thereby enabling the customer to download pertinent information about the component, such as lot number, date of manufacturer, test parameters, etc. The tags can be applied to the component immediately after manufacture and can be subjected to the sterilization process without risk of data loss or corruption. The memory device within the tag utilizes a technology that does not rely upon charge storage as its mechanism to store information.
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BACKGROUND OF THE INVENTION
The present invention relates to an apparatus and a method for producing measurement data concerning respiration-related movements of the abdominal wall and/or the thorax of a person. In particular, the present invention relates to a technical teaching the subject of which is the specified detection and monitoring of the respiratory activity of a person.
Breathing in (inspiration) is known to take place through expansion of the thoracic-pulmonary space by the respiratory muscles and through the resulting development of an alveolar partial vacuum in the expanding lung, leading to an inflow of air until pressure is equalized. Breathing out (expiration) takes place predominantly through a passive contraction of the thoracic space by a lowering of the thoracic cage and by an elasticity-related volumetric reduction (retraction) of the lung whereby air flows out as a result of the production of relative alveolar overpressure. Typical disorders of this human breathing process result, for example, from a reduction in lung elasticity or through narrowing of the apertures of the bronchial branches (restrictive or obstructive ventilation disorders), and from possible disorders of the respiratory centre, of diffusion or blood circulation in the lung.
Diaphragmatic respiration is the component of respiration resulting from contraction of the diaphragm (approx. two-thirds of breathing volume).
Attempts to detect and measure a respiration-related expansion of the thoracic and abdominal area during respiration in humans are known from the prior art. Sensors used typically for this purpose operate on piezoelectric principles and generate a comparatively low voltage as the output signal, a force being exerted on such a sensor through the respiration-related expansion of the thoracic or abdominal area during a breathing movement. By suitable processing a respiration signal is generated from a voltage signal produced thereby.
Other systems known from the prior art operate on an impedance principle, i.e. by making use of suitable resistor elements the electrical resistance of which changes through (respiration-related) movements of the thorax or the abdominal wall; in particular strain gauges or suchlike sensors are used for this purpose.
Known approaches of this kind have, however, the disadvantage that only a general detection of human breathing signals is possible, the quality and resolution of the electronic signal obtained normally being insufficient to permit monitoring of further body parameters at acceptable cost and without separate, additional sensors.
In view, in particular, of an inherent biological connection between respiration and cardiac activity it would therefore be desirable to be able to monitor both parameters simultaneously at low cost, and in particular with the use of only one sensor or one sensor arrangement. The same applies to the movement or activity of the person, as could be desirable in particular in the field of the observation of sporting activities.
It is therefore the object of the present invention to provide an apparatus for generating measurement data concerning respiration-related movements of the abdominal wall and/or the thorax of a person which is improved with respect to signal resolution and measurement accuracy in generating a respiration display signal and which therefore also offers, in particular, possibilities of detecting from this respiration display signal further parameters or superposed signals, and creates the possibility of generating with the same sensor system, in addition to data derived from respiratory movement, further data corresponding to other body parameters and functions, including heartbeat.
SUMMARY OF THE INVENTION
The foregoing object is achieved by an apparatus for generating measurement data concerning respiration-related movements of the abdominal wall and/or the thorax of a person, comprising at least one first pair of sensor units which are configured for detachable fixing on the skin on a thoracic or abdominal area of the person and are spaced apart by a first distance, and comprising a measuring device connected to the first pair of sensor units and configured for detecting signals of the sensor units which are capable of electrical evaluation and for generating a first distance signal corresponding to said first distance and changes in same, wherein an evaluation unit is connected to the output of the measuring device and is so configured for evaluating pulsed and/or waveform changes of the first distance signal that periodic signal changes of a frequency in the range between 0.05 and 0.1 Hz can be detected, distinguished in terms of frequency, amplitude or signal form from periodic changes of the first distance signal caused by the human heartbeat and outputted as a respiration display signal which can be electronically displayed or further evaluated. The object is further achieved by a method comprising the steps of continuous measurement of a first distance between two first sensors attached on the skin of the person on a thoracic or abdominal area, evaluation of electronic signal changes in the first measurement signal corresponding to changes in the first distance, and outputting of a respiration display signal as a reaction to a periodical signal change in the range between 0.1 and 0.5 Hz.
The present invention for data acquisition concerning respiration-related movements of the abdominal wall and/or the thorax of a person makes use in an inventively advantageous manner of the principle of data acquisition by measuring the distance between a pair of sensor units, changes in the distance between the sensors of the kind induced by the respiration-related movements to be detected generating the first distance signal according to the invention, which can be appropriately evaluated. In this context the fixing of the sensors to the skin is to be understood as a fixing of the sensors above the skin or body surface in such a way that a change in the distance between them can be detected from a pair of measuring points; it is therefore also provided in particular according to the invention to attach the sensors to the skin via an intermediate layer—a garment, a fabric or the like.
This principle for generating the first distance signal corresponds to that described in German Patent Application No. 42 14 523 and is realized in a manner known as such by means of a transmitter-receiver system based on ultrasonic or electromagnetic waves; with regard to an electronic constructional implementation of the distance measurement means the above-mentioned Patent/Patent Application DE 42 14 523 is to be regarded as included in its entirety in the present Application and as forming part of the invention.
The principle of ultrasonic distance measurement whereby the differences in travel time of the ultrasonic signal between the sensor units are measured and evaluated has proved advantageous for the implementation of measurement data generation concerning respiration-related movements according to the invention; alternatively, it is possible to utilize and evaluate phase differences between the transmitted and received signal.
According to the present invention this known technology now finds application to the particular requirements of measuring a respiration-related movement of the abdominal wall and/or the thorax, the distance-dependent capture of measurement data relating to movements of the thorax having proved to be especially reliable and accurate in conjunction with the evaluation unit provided according to the invention. Advantageously, this procedure according to the invention not only permits (general) testing for the presence of a breathing movement (which takes place according to the invention through the signal-related or time-related discrimination made possible by the evaluation unit), but the invention also offers the possibility—especially if a plurality of pairs of sensors are provided according to a refinement of the invention—of detecting with high resolution the thoracic movements induced by respiratory movements together with their temporal, local and spatial propagations, thereby making possible an investigation as to whether a respiratory process as such might possibly be pathological (if, for example, a detected, high-resolution form of the respiration signal fails to correspond to a norm).
It has also been shown in the context of the invention that the signal-form of normal breathing in the signal-time diagram is symmetrical, i.e. the rising and falling slopes of a breathing signal measured by distance change according to the invention are disposed symmetrically with respect to a mean value. It is therefore preferred, according to a refinement of the invention, to associate with the evaluation unit signal-form detection means which, for discrimination from other signals (such as artifacts generated by sensor movement, body position signals or cardiac motions) detect with high accuracy and low sensitivity to interference the presence of respiratory activity and further improve display accuracy.
According to a further, preferred refinement (best mode) at least two pairs of sensor units are provided which, in a manner further preferred, in each case span intersecting distances (e.g. approximately at a right-angle) and irradiate the thorax or abdominal area. The respiration-induced, locally (and in some cases temporarily) different thoracic movements can be accounted for especially advantageously in this way and evaluated for still more accurate measurement, e.g. by summation or subtraction of the signals obtained from the two pairs of sensors.
In addition, it is in general included within the present invention to align the sensor units of a given pair of sensor units either in such a way that a connecting line runs outside or along a periphery of the thorax and/or the abdominal area, or to cause the connecting line to pass longitudinally or diagonally through the thorax and/or the abdominal area.
According to a preferred refinement of the invention it is provided, in addition to the respiration-induced signal captured and outputted according to the invention, to capture a heart rate signal of the person to be monitored, this being done in the context of the invention likewise by evaluation of the distance signal obtained through the distance measurement according to the invention. As has advantageously been shown, cardiac activity (having a frequency in a range of typically approx. 1 Hz) also gives rise to periodic movements of the thorax, although the signals can, in the context of the invention, be reliably discriminated in terms of frequency and/or amplitude from the distance signals characteristic of respiration. Additional active monitoring of cardiac activity, in combination with respiration monitoring, therefore not only makes it possible to increase, for example, the diagnostic value of the respiration signal itself, but also allows reliable detection of further critical states of the person, such as sleep apnea or respiratory sinus arrhythmia, thereby allowing any required counter-measures to be taken in good time. Advantageously, there is no necessity for additional sensors for heartbeat detection which, in addition to incurring equipment costs and causing potential problems in fixing them to the patient, would present additional obstacles to a common signal evaluation process using a respiration-dependent signal.
According to a further preferred refinement of the invention it is provided that the first distance signal is evaluated to identify signal changes caused by shocks such as those produced by walking, running or hopping of the person, which, as has been found in the context of the present invention, can also be reliably detected and discriminated from the respiration display signal (especially because, in the case of typical step frequencies in the range of approx. 2.5 Hz, the signals can already be reliably distinguished in their frequency range from the changes in the first distance signal characteristic of breathing and cardiac activity). An additional, active monitoring of step frequency made possible by this refinement of the invention therefore also permits states of the physical activity of the person, such as the training state, and dependences between heart rate, respiration frequency and step frequency, to be reliably detected and analyzed, and subsequent diagnostic measures to be taken. If heart rate signals and step frequency signals are in the same range, they can be discriminated by different amplitudes.
According to a further preferred refinement of the invention it has emerged that a generating curve of an envelope of the respiration display signal, and in particular the upper and lower limit values of this curve (which correspond to a maximum and a minimum distance between the pair of sensor units), characteristically change when the person changes his/her position, for example, in a sleep position—turning, for example, from lying on their back to lying on their side. According to a suitable refinement, an evaluation of these generating curve parameters over a typical period of several minutes therefore additionally makes it possible to derive position data relating to the person from the distance signal.
The present invention is especially suited to use in conjunction with a portable unit co-operating with a base station for data transmission which, an a manner further preferred, is effected wirelessly. The present invention makes it possible to provide the units for data acquisition and evaluation made available according to the invention, which are usually realized by means of suitably programmable controllers, in a portable, battery-powered housing which can be carried about continuously by the person monitored and which makes possible permanent monitoring of respiratory activity, the physical activity of the person and heart rate. Included here is the compilation of a respiration and stress profile (sleep, stress) and observation of respiration as a function of various parameters.
It should be clear that an instrument and a method are created by the present invention which are not only adapted rapidly to distinguish critical from normal breathing states in a simply-evaluated and highly reliable manner (therefore making it possible both to provide rapid assistance and to avoid superfluous dispensing of medication); in addition, through a portable realization of the invention an extremely advantageous instrument for increasing flexibility and convenience in the monitoring of respiratory activity is provided.
As is also achieved by the present invention, a combined analysis of different body functions including respiration, cardiac activity and physical activity can be generated with simple means, and detailed statements on the general condition of a monitored person can be made.
Further advantages, features and details of the invention are apparent from the following description of preferred embodiments with reference to the drawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view of the apparatus according to the invention for generating respiration-induced measurement data according to a first embodiment of the invention as a block diagram showing the major functional elements and their interaction;
FIG. 2 is a schematic illustration showing an anterior view of the body of a person with the apparatus according to FIG. 1 attached;
FIG. 3 is a posterior view according to FIG. 2 ;
FIGS. 4 to 9 are different schematic illustrations showing the fixing of one or two pairs of sensor units and the definition of the first distance, in the form of pairs of schematic sectional views through the upper part of a human body showing the contracted and the expanded state of the lung;
FIG. 10 is a signal/time diagram to clarify the first distance signal and its changes in a rest state;
FIG. 11 is an illustration according to FIG. 10 , but while the person is running;
FIG. 12 shows the respiration display signal in enlarged time-resolution to clarify superposed signals (person standing);
FIG. 13 is a representation analogous to FIG. 12 with the person hopping;
FIG. 14 is a representation analogous to FIGS. 10 to 13 , but including various respiration processes and a crossed sensor arrangement analogous to FIGS. 8 , 9 ;
FIG. 15 is an enlarged illustration of a section of the right-hand portion of the signal curve of FIG. 14 ;
FIG. 16 is a signal/time diagram to clarify the respiration display signal during sporting activity (skating); sensor arrangement according to FIG. 8 , FIG. 9 ;
FIG. 17 is a signal/time diagram of a recording over approx. 50 minutes of measurement data for a sleeping person with change of the sleeping position, and
FIG. 18 is an enlarged representation of a section of the view according to FIG. 17 showing the sleep display signal during sleep.
DETAILED DESCRIPTION
FIG. 1 clarifies in a block diagram the way in which two pairs of sensor units 12 , 14 and 16 , 18 of an ultrasonic distance measuring unit 20 are associated inside a portable housing 10 , the ultrasonic distance measuring unit 20 emitting in an otherwise known manner—approximately as described in Patent Application DE 42 14 523 referred to above—a corresponding signal suitable for further evaluation on the basis of travel time differences during changes in a distance 1 (between sensor units 12 , 14 ) and a distance 3 (between sensor units 16 , 18 ; in addition, a third distance 2 between a sensor unit of the first pair and a sensor unit of the second pair is captured).
In concrete terms, as is shown in FIG. 1 , an evaluation and outputting unit 22 is connected to the output of the distance measuring unit 20 and generates the respiration display signal, which it sends to a display unit 28 , preferably a monitor, as a reaction to the distance measurement signal (formed by summation or as a difference signal) of the unit 20 by suitable frequency filtering (preferably effected by calculation from the signal curve) in the range of 0.1 to 0.5 Hz. The evaluation unit is configured for additionally generating a pulse display signal which is generated as a reaction to the detected changes in the first distance signal caused in terms of frequency, amplitude and/or signal shape by the human heartbeat, in particular, in a frequency range of between 0.8 and 2.5 Hz.
In parallel thereto a digital signal pattern of the respiration display signal is stored for later evaluation or correlation with other measurement value curves in a memory unit 26 , and a connection of the respiration monitor, as shown in FIG. 1 and realized in the simplest manner, to a wirelessly-connected base station by means of a transmission antenna 30 takes place via a communication unit 24 shown only schematically (and realized in practice, for example, by a currently-used GSM mobile phone unit) for further monitoring and evaluation. The memory unit comprises analysis and storage means associated with the evaluation unit, which are configured for electronically storing the respiration display signal and for detecting a change in terms of amplitude, frequency and/or signal form of the respiration display signal. The analysis and storage means are configured for generating a correlation signal between the respiration display signal and the pulse display signal.
The measuring device and the evaluation unit are components of a portable battery-powered unit 10 which is connectable to a stationary base unit by a wireless data connection for transmission of the display signal and/or further signals. The evaluation unit is configured for additionally detecting a change in the first distance signal generated by running or hopping of the person, and to determine a stepping or hopping frequency therefrom. Furthermore, the evaluation unit is configured for detecting a generating curve of the envelope of the first distance signal over a time interval which is long in comparison to a breathing frequency, and for determining a change in a lower and/or upper limit value of said generating curve.
FIGS. 2 and 3 show how the apparatus shown schematically in FIG. 1 is operated in practice. A belt 40 is attached in the thoracic area to the schematically illustrated body of a patient, with which belt 40 both the housing 10 and the four sensors 12 to 18 can be so attached to the body of the person that said sensors 12 to 18 can cooperate for reciprocal distance measurement.
Referring now to FIGS. 4 to 9 , a number of possible ways of attaching both one and two pairs of sensor units to the body in the manner sketched in FIGS. 2 , 3 , so that signals well suited to evaluation are attainable, will be discussed by way of example below. In the illustrations of FIGS. 4 to 9 the sensors of one or two pairs of sensor units are in each case represented as circles, and the arrows connecting these circles mark the distances relevant to distance measurement or the generation of distance signals. The illustrations are horizontal cross-sections through the thoracic area at the level of the belt 40 in FIGS. 2 , 3 , a spinal column 42 being indicated schematically in the posterior area and the heart 44 in the left anterior area.
FIG. 4 clarifies schematically the fixing of only one pair of sensor units jointly to an anterior thoracic area of the person so that the length marking the distance (arrow 1 ) is located on the periphery of the body. Whereas the contracted state of the thorax is shown in FIG. 4 , the sensor units are attached in a corresponding manner in FIG. 5 , but here the thorax is expanded after inspiration.
FIGS. 6 and 7 (contracted and expanded state) clarify an alternative manner of fixing a pair of sensors. In this case a first sensor of the pair is arranged in the anterior thoracic area and the second in the posterior area, so that the length (arrow 1 ) marking the distance extends through the body. The increased distance between the sensors achieved thereby makes it possible in some cases to achieve a further improved resolution of the respiration-induced distance signal as compared to the illustration in FIGS. 4 , 5 .
FIG. 8 shows a configuration having two pairs of sensor units which are arranged crosswise in the manner shown in the thoracic and back area; to this extent the sensor arrangement in the sectional views according to FIG. 8 , FIG. 9 (again in the contracted and expanded states) corresponds to the sensor arrangement shown in FIGS. 2 and 3 and to the designation of the distances 1 , 2 , 3 between the individual sensors according to FIG. 1 . Here, use is also made of the fact that an additional measurement distance 2 is formed between the sensor units 14 (of the first pair 12 , 14 ) and 16 (of the second pair 16 , 18 ), which can be realized in practice either by means of ultrasonic sensors having a plurality of sensor elements (crystals), by a plurality of sensors fixed in one place, or by a connection and evaluation such that in each case one transmission element is always opposite one receiving element (for example, in the illustration according to FIGS. 8 and 9 , 12 could be a transmitting element and 14 a receiving element, 16 could again be a transmitting element and 18 a receiving element, so that a transmission-reception path for evaluation is also formed between 14 and 16 ).
Through appropriate summation or subtraction an optimized signal resolution can be achieved, especially for the configuration shown in FIGS. 8 , 9 , which signal resolution, as will be discussed below with reference to signal curves, can be resolved into numerous parameters and detailed information and evaluated in terms going beyond the simple presence of respiration.
The representation in FIG. 10 shows a total of five breathing cycles, each breathing cycle being characterized by a rising slope 60 , a maximum signal area 62 and a descending slope 64 , so that, independently of the depth of breathing—the first two breathing cycles in the illustration according to FIG. 10 represent normal cycles, the middle cycle is a long, especially deep breathing cycle and the two breathing cycles on the right are short, shallower breathing cycles—a symmetrical signal form is produced in the time domain (an axis of symmetry 66 is drawn for the first signal as an example).
As compared to the illustration in FIG. 10 , the diagram in FIG. 11 , obtained while the person measured was running, shows a characteristic superposing of the respiration signal on a change signal in the range of the running frequency (approx. 2.5 Hz); the signals, which are shorter in comparison to the respiration cycle (although the latter is accelerated by running) are denoted by reference numeral 66 in FIG. 11 .
As is shown in FIG. 11 , the present invention makes it possible not only to record the respiration signal during physical movement of the person (running, hopping, etc.); because of the impacts occurring upon contact with the ground a slight displacement of the sensor elements in the running or hopping rhythm additionally occurs, these impact peaks being clearly visible in FIG. 11 . This superposed signal can, however, be easily separated with regard to both frequency and amplitude from the underlying respiration signal (in order to carry out a separate evaluation), and it also appears possible to transfer this evaluation concept to other applications (cycling, in-line skating or the like) within the scope of the invention.
In the context of the embodiment described according to FIG. 1 , evaluation of this stepping frequency is carried out by means of a separate evaluation unit 34 which is associated with the evaluation and display unit 28 .
FIG. 12 shows in larger resolution in the signal-time diagram the respiration display signal of a standing person (analogous to FIG. 10 ); FIG. 13 corresponds with regard to resolution to FIG. 11 and shows respiration display signals when hopping. Superpositions 66 induced by the impacts are again clearly seen.
FIG. 14 illustrates a respiration display signal using a sensor arrangement (as in FIGS. 6 , 7 and FIGS. 8 , 9 ) in which the effective distance between a pair of sensor units is maximized to improve signal resolution. With his improved resolution the depth of breathing, in particular, can be recognized and distinguished. Thus, the breathing cycles located on the left in FIG. 14 show a waveform characteristic of deep breathing; the following, signal-free time interval corresponds to the pause in breathing after expiration, the following two signals of lower height correspond to normal (less deep) breathing, and the extended and high signal pulse located on the right corresponds to a deep inspiration and subsequent holding of the breath.
FIG. 15 , which shows an enlargement of a section of the deep and sustained breathing cycle located on the right in FIG. 14 , clarifies how superposed heartbeat pulses 68 are recognizable in the signal and can be additionally detected and evaluated by suitable discrimination of frequency and/or amplitude. For this purpose a separate discrimination and evaluation unit 32 , which detects heart rate in a manner known as such by (preferably numerical) evaluation of a signal curve as in FIG. 15 , is associated with the evaluation and outputting unit 22 in FIG. 1 .
FIG. 16 shows a further example of a respiration display signal during sporting activity (here: skating), while FIG. 17 (long-time measurement over approx. 50 minutes) and FIG. 18 (resolution from FIG. 17 in individual respiration cycles) illustrate breathing signals of a person while asleep.
As has been interestingly shown by (preferably numerical) evaluation of the envelope-generating curve over a period of several minutes according to FIG. 17 , position changes of the sleeper (e.g. turning from the back to the side position) give rise to a characteristic jump (reference numeral 70 in FIG. 17 ) in the envelope-generating curve of the respiration display signal or, more precisely, cause the minimum distance to change abruptly and permanently. Accordingly, through appropriate (preferably numerical) evaluation of the envelope-generating curve such a position change of the sleeper can be detected from the distance signal, which is present in any case, and can be included in further evaluations as a basis for diagnostic purposes.
It can be seen from a consideration of the examples of embodiments and applications, therefore, that the present invention offers potential for a large number of possible applications; these extend from long-time respiration measurement and long-time activity measurement through a taking account of respiration, pulse and movement data in biofeedback and in stress management, through controlled breathing exercises for pregnant women, pace counting while jogging, monitoring of respiration disorders of the most diverse kinds (including monitoring of SIDS, sudden infant death syndrome) to the identification of circulation parameters under stress (including energy conversion measurement), such as the pulse-respiration quotient, all of which is achieved through the evaluation of a single distance signal, admittedly of high-resolution and therefore highly informative, obtained according to the present invention. In addition to the frequency and depth of breathing (where a connection with pulmonary volume exists), therefore, respiration variability can also be detected as a determinable value; through suitable positioning of the sensor units differences between the efficiency of the right and left pulmonary lobes, differences between diurnal and nocturnal activities with regard to breathing, pulse, etc., position changes during sleep, stepping frequency and heart rate (in order to deduce the energy conversion of the person from a combination of breathing and heart rate) and a relationship between abdominal breathing and thoracic breathing, can likewise be detected as determinable values.
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An apparatus for producing data concerning the respiration-related movements of the abdominal wall and/or the thorax of a person. The device comprises at least one first pair of sensor units ( 12, 14 ), which are configured for detachably fixing on the skin in an area of the person's thorax or abdomen, a first distance ( 1 ) apart; and a measuring device ( 20 ) which is connected to said first pair of sensor units and which is configured for detecting signals of the sensor units that can be evaluated electrically and for producing a distance signal corresponding to the first distance ( 1 ) and to changes in the same. Connected downstream of the measuring device is an evaluation device ( 22, 28 ) which is configured for evaluating pulsed and/or wave-shaped changes in the first distance signal, in such a way that periodical signal changes of a frequency in the range of 0.05 to 0.1 Hz are detected, distinguished from the periodical changes in the first distance signal that are due to the human heartbeat in terms of frequency, amplitude or signal shape and output in the form of a respiration display signal that can be displayed and further processed electronically.
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BACKGROUND OF THE INVENTION
As recognized in the art, opal glasses contain small particles which scatter light passing through the glass, thereby rendering such glasses light diffusing. Hence, opal glasses will always consist of a transparent glassy matrix and at least one other phase dispersed therewithin. The dispersed phase(s) may be either crystalline or amorphous. The primary characteristics of the dispersed or opacifying phase which determine the density of light transmission include the refractive index, the dispersion, the size and shape of the particles, the particle distribution, and the absolute number of particles.
There are two broad classes of opal glasses, viz., spontaneous opals and thermally opacifiable or reheat opals. Spontaneous opal glasses are characterized by the fact that the light-diffusing phase separates out ("strikes in") during the cooling and forming of the melt into a glass article. In contrast, the rate of opal development, i.e., the rate at which the light-diffusing phase separates out of the glassy matrix, is relatively slow in the thermally opacifiable glasses. Consequently, upon cooling and shaping the melt into a glass article, a substantially clear or only faintly opacified appearance is observed. The glass article must be reheated to temperatures in and/or above the transformation range of the glass to promote separation of the opacifying phase(s). It will be appreciated that, from a commercial point of view, spontaneous opal glasses are much to be preferred since no reheating is demanded to achieve the desired opacity.
There are two general categories of spontaneous opal glasses, the first being characterized as having an amorphous (non-crystalline) opacifying phase and the second having a crystalline opacifying phase. The first type has been termed immiscible opals, i.e., opals wherein the opacifying phase is a glass which is not soluble in the matrix. The most ommon immiscible opals contain borate or phosphate in the opacifying phase. U.S. Pat. Nos. 2,559,805 and 3,275,492 are illustrative of those. U.S. Pat. No. 3,661,601 describes another immiscible opal containing phase separated droplets or opacifying particles consisting of CaO and F or CaO, F, B 2 O 3 , and SiO 2 . Numerous crystals have been precipitated to constitute the opacifying phase, the most common being either an alkali metal fluoride (most frequently NaF) or an alkaline earth metal fluoride (most often CaF 2 ).
In summary, a spontaneous opal glass attains the vast majority of its opacity during the cooling of the melt to a glass article and requires no reheating. Thus, the opacifying agent strikes in during the shaping of the melt to a glass article utilizing such conventional glass forming techniques as blowing, casting, drawing, pressing, rolling, and spinning.
SUMMARY OF THE INVENTION
The present invention defines a narrow range of compositions within the Na 2 O-K 2 O-BaO-Al 2 O 3 -B 2 O 3 -SiO 2 -P 2 O 5 -F system which provide spontaneous opal glasses manifesting dense white opacity and excellent chemical durability, i.e., high resistance to attack by water, food acids, and detergent solutions, thereby recommending their utility in food service applications. Thus, the base glass compositions, expressed in terms of weight percent on the oxide basis, consist essentially of 6-10% Na 2 O, 1-6% K 2 O, 4-11% BaO, 9-18% Al 2 O 3 , 1-5% B 2 O 3 , 50-70% SiO 2 , 3.5-7% P 2 O 5 , and 1-4% F. Optionally, the glasses may also contain up to about 3.5% CaO and/or up to 5% total of SrO and/or MgO to modify the melting and forming character of the glass as well as the physical properties thereof. Nevertheless, the sum of those three ingredients plus any other extraneous components will not exceed about 5% by weight. A barium fluorophosphate-type crystal phase constitutes the opacifying agent. The appended electron micrograph illustrates this crystal phase interspersed in the glassy matrix, the arrows indicating the presence of spherules containing the crystal phase.
The glasses of this fluorophosphate opal system are characterized by a two-stage liquidus phenomenon. A high temperature cloudiness or opacification has been observed which can be characterized as an emulsification or liquid-liquid phase separation. Analysis of the separating phase has indicated it to be rich in Na 2 O, BaO, P 2 O 5 , and F. The normal crystallization opal liquidus occurs in the range of about 400°-1000° C., depending upon the relative concentration of the aforementioned species. X-ray diffraction analyses of the crystalline opal phase have identified the predominant crystal phase to be of a Ba 2 (OH)PO 4 type. However, it is assumed that F easily substitutes for OH in this species. X-ray analysis does not distinguish between F and OH. Accordingly, the phase has been termed Ba 2 F(PO 4 ). Minor amounts of NaBaPO 4 and other presently-unidentifiable species have also been detected. Those glasses exhibiting low temperature crystallization opal liquidi have the capability of striking in further during the annealing process. The most desirable glass would remain essentially clear during the forming steps and then opacify in the course of annealing. Such glasses would be free from differential opacification, a problem sometimes encountered with glasses demonstrating high opal liquidus temperatures. It has been noted, however, that in some instances glasses having low temperature opal liquidi are also subjected to surface crystallization developed during the annealing heat treatment. That occurrence leads to a substantial loss of glossy appearance in the final product and/or reduced chemical durability as witnessed in detergent testing.
The inventive fluorophosphate opal glass system is composition sensitive with regard to maintaining the desired combination of excellent chemical durability and resistance to weathering, high softening point, and dense white opacity. High levels of Al 2 O 3 are crucial in achieving the desired detergent durability, as evidenced in resistance to alkali attack, and in substantially eliminating weathering. It is conjectured that Al 2 O 3 densifies the glassy matrix, thereby inhibiting gross migration of Na + and F - ions to the glass surface. The content of Na 2 O ought not to exceed about 10% to insure high resistance to weathering. Amounts of Na 2 O in excess of 10% also tend to raise excessively the coefficient of thermal expansion, lower the softening point, and, where present in quantities greater than 14%, decrease opacity. A minimum softening point of about 710° C. has been deemed necessary to permit the use of satisfactory enamel fluxes in the decoration process. However, high toxic metal releases from softer (lower temperature) enamels preclude the use for food service ware of substrate glasses having softening points substantially lower than about 780° C. Accordingly, glasses having softening points of at least 780° C. are greatly to be preferred.
Minimum levels of 3.5% P 2 O 5 and 4% BaO are demanded to achieve the desired opacity. Dense opacity is ensured with 5-10% BaO. Excessive quantities of BaO impart two deleterious effects. First, the microwave susceptibility of the glass greatly increases, thereby hazarding breakage in a microwave oven. Second, the density of the glass increases sharply, thereby yielding heavy finished ware. Excessive concentrations of P 2 O 5 can adversely affect the chemical durability of the glasses and the meltability of the glass.
The reactive contents of Na 2 O, BaO, P 2 O 5 , and F govern the identity of the principal crystal phase. A minimum level of 1% F retained in the glass is adequate to generate the fluorophosphate phase and to hold the working or forming temperatures at about 1325° C. or below. A 2-3% F content is preferred to maximize opacity and whiteness and to decrease the forming temperature. Such levels of F are also much less polluting of the environment than the conventional NaF and CaF 2 opal glasses of commerce which customarily employ 5% and more F. In the present glass compositions, about 70-80% of the fluoride in the batch materials will be retained in the shaped glass articles. Fluoride exerts a profound effect upon the viscosity of the glass as indicated by the softening point. For example, a 1% addition of fluoride to the base glass composition yields an increase in the softening point thereof of about 50° C. Consequently, adjustments of fluoride content provide for a wide latitude of softening points. It is postulated that this pronounced dependence of the glass upon fluoride levels reflects the fluorine atom entering the matrix of the glass structure.
B 2 O 3 and K 2 O are important fluxing agents in the inventive glasses. In contrast to Na 2 O, B 2 O 3 or B 2 O 3 together with K 2 O can be used to decrease the coefficient of thermal expansion of the glasses. These components are included to insure a high temperature working viscosity corresponding to about 1325° C. or lower. Hence, elimination of K 2 O or B 2 O 3 causes a dramatic increase in the high temperature working viscosity unless the Na 2 O content is raised proportionately. Such action adversely affects the expansion and durability of the glasses. Nevertheless, the level of K 2 O should not exceed about 6% because opacity appears to decrease due to the increased fluxing behavior exerted by the oxide. Thus, the opacifying crystal phase seems to be much more soluble in the K 2 O-enriched matrix glass. Furthermore, and very importantly, the quantity of B 2 O 3 ought to be maintained below 5% to forestall solubility of the crystal phase.
Concentrations of CaO in excess of 3% and MgO and/or SrO greater than 5% result in the glasses displaying very high emulsion liquidus temperatures coupled with opacification in the melt. Hence, high levels of those ingredients lead to devitrification of the glass. Thus, calcium and strontium phosphates are significantly less soluble in the glass matrix than are sodium barium phosphate or barium fluorophosphate. As a result, ware formed from such opal glasses demonstrate "mother-of-pearl" or iridescent surfaces, this phenomenon being derived from light refraction in the elongated crystals forming on or near the surface of the glass. Small quantities of CaO, MgO, and/or SrO can be useful in modifying the physical properties of the glass while not substantially altering the opacity or chemical durability thereof.
Where a colored opal glass is desired, conventional glass colorants, such as CoO, Cr 2 O 3 , CuO, Fe 2 O 3 , MnO 2 , NiO, and V 2 O 5 may be included in customary amounts, normally less than about 2%.
PRIOR ART
U.S. Pat. No. 2,394,502 describes the production of opal glasses containing fluorapatite [3R 3 (PO 4 ) 2 .RF 2 ], wherein R is selected from the group of Ca, Ba, and Pb, as the primary crystalline opacifying phase. The glasses consist essentially, in weight percent on the oxide basis, of 12-17% Na 2 O+K 2 O, up to 12% CaO, up to 4% BaO, up to 5% PbO, 0-6% Al 2 O 3 , 0-50% B 2 O 3 , 4-9% P 2 O 5 , 54-66% SiO 2 , and 2.5-5% F. The Al 2 O 3 content of the patented glasses is far below that required in the compositions of the instant invention plus the crystalline opacifying phase is different from the Ba 2 F(PO 4 ) species of the inventive glasses.
U.S. Pat. No. 2,559,805 discusses the production of opal glasses containing Ba 3 (PO 4 ) 2 as the predominant crystalline opacifying phase. The glasses consist essentially, in weight percent on the oxide basis, of 7-15% alkali metal oxide, 5-25% BaO, 0-25% B 2 O 3 , 2-10% P 2 O 5 , 0-10% Al 2 O 3 , and 50-70% SiO 2 . Fluoride is nowhere indicated as being part of the glass composition so, consequently, the crystalline opacifying phase cannot be Ba 2 F(PO 4 ).
U.S. Pat. No. 3,275,492 discloses the production of opal glasses consisting essentially, in mole percent on the oxide basis, of 10-27% B 2 O 3 (equivalent to 12-30% by weight), 66-81% SiO 2 (equivalent to 62-76% by weight), 3-24% of an oxide selected from the group of ZnO, MgO, CaO, BaO, NiO, MnO, CoO, and CuO, and 1-7% alkali metal oxide. It is observed that, optionally, up to 4 mole percent F, up to 2 mole percent P 2 O 5 , or up to 5 mole percent may be included. The B 2 O 3 contents are much higher than those that can be tolerated in the instant inventive glasses. Furthermore, there is no teaching of the presence of any crystalline opacifying phase.
U.S. Pat. No. 3,498,801 relates to the production of opal glasses wherein opacification results from a liquid-liquid separation of a phosphate phase from the glass matrix. The glasses consist essentially, in weight percent on the oxide basis, of 9-13.5% alkali metal oxides, 1-2% CaO, 0-1.5% BaO, 5-12% B 2 O 3 , 4-8% Al 2 O 3 , 3-5.5% P 2 O 5 , and 60-68% SiO 2 . Fluoride is not a constituent of the glasses, the Al 2 O 3 content is lower and the B 2 O 3 level higher than demanded in the instant inventive glasses. Moreover, the opacifying phase in the patented glasses is non-crystalline.
U.S. Pat. No. 3,661,601 is concerned with opal glasses wherein glassy particles comprise the opal phase which consist essentially, in weight percent on the oxide basis, of 3-10% Na 2 O+K 2 O, 11-20% CaO, 0-10% BaO, 3-9% Al 2 O 3 , 1-7% B 2 O 3 , 0-10% P 2 O 5 , 50-75% SiO 2 , and 2-4% F. The concentration of CaO is much higher and the Al 2 O 3 content lower than required in the instant inventive glasses. Furthermore, the opacifying phase in the patented glasses is non-crystalline.
U.S. Pat. No. 3,667,973 is directed to opal glasses wherein the opal phase is in the form of encapsulated crystalline droplets of NaF, LiF, and/or KF, possibly containing B 2 O 3 as an impurity. The glasses consist essentially, in weight percent on the oxide basis, of 1.5-4% Li 2 O, 0-10% Na 2 O+K 2 O, 0-1% BaO, 1-3% Al 2 O 3 , 7-14% B 2 O 3 , 0-10% P 2 O 5 , 70-80% SiO 2 , 1-3% MoO 3 and/or As 2 O 3 and/or WO 3 , and 3-6% F. The B 2 O 3 level is higher and the BaO and Al 2 O 3 concentrations much lower than useful in the instant inventive glasses. Also, the opacifying phase in the patented glass is not Ba 2 F(PO 4 ).
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Table I records glass compositions, expressed in terms of parts by weight on the oxide basis as calculated from the batch, illustrating the compositional parameters of the instant invention. Inasmuch as it is not known with which cation(s) the fluoride is combined, it is merely reported as fluoride (F) in accordance with conventional glass analysis practice. Moreover, because the sum of the several components totals or approximately totals 100, for all practical purposes the values tabulated may be considered to be expressed in terms of weight percent. Where desired, an oxide of arsenic or a chloride salt can be included in the batch to perform their customary function of a fining agent.
The actual batch ingredients may comprise any materials, either the oxides or other compounds, which, when melted together, will be converted into the desired oxide in the proper proportions. The fluoride will typically be added as sodium silicofluoride. Whereas the following description reflects laboratory and pilot plant scale melting, it will be understood that the recited compositions would also be operable in large scale commercial melting units.
The batch ingredients were compounded, tumble mixed together to aid in securing a homogeneous melt, and placed into platinum crucibles. The crucibles were introduced into an electrically-fired furnace operating at 1450°-1550° C. and the batches melted for four hours (after last fill). The melts were then cast into steel molds to produce slabs about 6"×6"×1/2" or manually pressed discs having a diameter of 3-4" and a thickness of 0.125-0.25". The pressed discs were undertaken as a rather primitive form of quick quenching such as is encountered in commercial automatic pressing. The glass slabs were immediately transferred to an oven operating at the annealing temperature, that temperature maintained for one hour, and then cooled to room temperature at furnace rate, i.e., at about 30° C./hour.
Additionally, 750-pound melts of certain glasses were made in gas-fired pilot plant furnaces, the glass hand gathered at 1200°-1400° C., depending upon viscosity, and hand pressed in cast iron molds with steel plungers. Baking dishes and dinner plates were formed in this manner and annealed in a lehr. Where desired, the ware was firepolished utilizing conventional practices.
Table II illustrates the retention of fluoride in the glass as analyzed.
TABLE I______________________________________ 1 2 3 4 5 6 7 8______________________________________SiO.sub.2 56.00 56.24 54.62 60.10 58.67 60.50 58.80 59.62Al.sub.2 O.sub.3 14.35 14.80 14.19 10.34 12.40 13.00 10.30 13.30Na.sub.2 O 8.02 8.20 7.85 8.60 8.39 8.50 7.10 8.51K.sub.2 O 4.50 5.95 5.70 4.82 4.73 4.50 5.40 2.05B.sub.2 O.sub.3 3.24 3.30 3.17 3.46 4.00 2.00 3.50 3.25P.sub.2 O.sub.5 5.99 4.10 3.91 4.26 4.18 5.00 5.10 4.14BaO 6.47 4.40 10.56 6.92 6.14 5.00 7.70 6.20CaO 1.42 3.06 -- 1.52 1.49 1.50 -- 1.54MgO -- -- -- -- -- -- 2.00 1.75F 4.28 2.20 2.20 2.20 2.20 2.25 2.70 2.21______________________________________ 9 10 11 12 13 14 15 16______________________________________SiO.sub.2 60.11 59.30 60.85 58.40 63.10 60.90 63.90 69.70Al.sub.2 O.sub.3 13.25 10.40 12.70 14.80 12.20 12.10 10.10 4.70Na.sub.2 O 8.51 8.10 8.75 8.20 9.70 8.50 7.80 10.00K.sub.2 O 3.46 2.70 2.60 1.90 -- 2.70 -- --B.sub.2 O.sub.3 2.41 4.60 1.00 3.33 3.10 -- 3.10 3.20P.sub.2 O.sub.5 4.04 5.20 4.10 4.10 5.30 5.50 5.20 5.50BaO 6.63 7.80 6.70 6.60 4.60 8.20 -- --CaO 1.59 -- 1.80 1.50 -- -- 2.10 2.20MgO -- 2.10 1.50 1.20 2.10 2.20 7.90 4.70F 2.19 2.80 2.25 3.00 1.70 3.30 1.70 1.80______________________________________ 17 18 19 20 21 22______________________________________ SiO.sub.2 58.83 60.00 63.05 64.50 55.10 62.30 Al.sub.2 O.sub.3 16.51 14.85 4.25 4.40 14.47 4.58 Na.sub.2 O 8.48 9.30 11.90 12.40 8.00 11.96 K.sub.2 O 4.72 -- -- -- 5.83 -- B.sub.2 O.sub.3 -- 3.35 4.70 4.90 3.23 2.60 P.sub.2 O.sub.5 4.18 4.10 5.30 7.80 3.99 5.31 BaO 5.68 6.70 -- -- 2.15 8.03 CaO 1.59 1.50 -- 6.10 -- -- MgO -- 1.16 -- -- -- 2.11 - SrO -- -- 10.80 -- 7.28 -- F 2.16 2.77 1.30 5.30 2.14 3.41______________________________________
TABLE II______________________________________ A B C D E______________________________________SiO.sub.2 56.36 56.36 56.36 56.36 56.36Al.sub.2 O.sub.3 15.84 15.84 15.84 15.84 15.84Na.sub.2 O 8.06 8.06 8.06 8.06 8.06K.sub.2 O 4.53 4.53 4.53 4.53 4.53B.sub.2 O.sub.3 3.25 3.25 3.25 3.25 3.25P.sub.2 O.sub.5 4.02 4.02 4.02 4.02 4.02BaO 6.51 6.51 6.51 6.51 6.51CaO 1.43 1.43 1.43 1.43 1.43F (batch) 3.76 2.96 2.15 1.61 0.81F (anal.) 2.87 2.19 1.61 1.24 0.57______________________________________
Table III reports softening points (S.P.) in terms of °C. and coefficients of thermal expansion over the range of 25°-300° C. (Exp.) in terms of ×10 -7 /°C. determined in accordance with measuring techniques conventional in the glass art. The development of devitrification (devit.) during the determination of the softening point is noted. High temperature viscosities were measured employing cooling rates of 2° C./minute.
High speed emulsion and crystalline opal liquidus data (°C.) were obtained utilizing a hot stage microscope composite apparatus.
Samples of the glasses were screened for potential weathering problems by boiling in water for six hours, wiping dry, and thereafter heating at 300° C. for 15 minutes. Glasses having any surface crazing or crizzling observed either macroscopically or microscopically were adjudged failures. Na 2 O extraction levels, determined after boiling a glass sample in distilled water for one hour, were also deemed to provide an indication of potential weathering problems. Hence, samples demonstrating Na 2 O extraction quantities less than 4 μg/cm 2 were considered to be desirably resistant to weathering.
An empirical visual estimation of the density of opacification is also recorded. The term dense signifies that the sample exhibited no translucency in the pressed ware or annealed slabs.
In conducting a test for determining the resistance of the inventive glasses to detergents, samples were immersed into a 0.3% aqueous solution of SUPER SOILAX® detergent, marketed by Economics Laboratories, St. Paul, Minnesota, operating at 95° C. for intervals of 24, 48, 72, and 96 hours. The surface areas of the samples were limited to the ratio of 12 square inches to one pound of the solution. The samples were removed periodically from the hot solution, rinsed in tap water, and wiped dry. A portion of each sample was coated with DYE-CHECK® dye penetrant, marketed by Magna-Flux Corporation, Chicago, Illinois, and the dye permitted to remain thereon for 20 seconds. Samples which manifested no dye penetration, i.e., no stain was evident after the dye was wiped clean with a dry cloth, were classified as "AA". Samples from which the stain could be removed with a cloth wetted with SUPER SOILAX® detergent, were categorized as "A". Samples from which the stain could be removed with a dampened cloth and a commercial powdered cleanser were tabulated as "B". Finally, samples from which the stain could not be removed via any of the above procedures were listed as "C". When samples received a rating of "B" or less, the testing was not continued. Where visual observation indicated a particular sample exhibited any loss of gloss in the testing, that sample was given a "loss of gloss" rating, which was considered to be equivalent to a "C" rating.
TABLE III__________________________________________________________________________ 1 2 3 4 5 6 7 8 9 10 11__________________________________________________________________________Opacity Dense Dense Dense Dense Dense Dense Dense Dense Dense Dense DenseS.P. 733 746 718 735 726 809 782 845 780 802 798Exp. 84.1 88.7 88.6 82.1 85.0 85.9 86.5 77.8 81.5 81.2 78.2Na.sub.2 O Extraction -- 4.1 2.5 -- 2.0 4.6 4.0 1.7 4.4 1.8 2.3Detergent 24 hrs A AA AA A* AA A A A A A ARating 48 hrs A AA A A* A A A-A* A A A A 72 hrs A* A A B* A A-B A-A* A A A A* 96 hrs -- A-C A -- A A-B A-A* A A A A*Lowest FormingTemp. - HandPressing (°C.) -- 1250 1215 -- 1205 1250 1280 1290 1345 1275 1290EmulsionLiquidus 1240 1060 1010 1180 1140 1200 1050 1170 1160 1150 1160CrystallineOpal Liquidus 1030 1100 570 500 700 695 650 700 600 650 520__________________________________________________________________________ 12 13 14 15 16 17 18 19 20 21 22__________________________________________________________________________Opacity Dense Dense Dense Dense Dense Dense Dense Dense Dense Dense DenseS.P. 780 815 -- 867 800 810 819 Devit Devit -- 770Exp. 81.0 -- -- 76.8 79.0 82.1 73.7 63.0 -- -- 85.1Na.sub.2 O Extraction 1.9 2.8 7.8 2.15 13.8 2.8 1.1 -- -- -- 15Detergent 24 hrs A A A A A* AA A A Scum A* ARating 48 hrs A A* A A A* A A A in the A* C 72 hrs A B* A* A -- A A B melt B* -- 96 hrs A -- -- A -- A A C -- --Lowest FormingTemp. - HandPressing (°C.) 1320 1280 1335 1380 1230 1300 1290 -- -- -- --EmulsionLiquidus 1150 -- 1100 1050 1000 1180 1110 1500 -- 1500 1340CrystallineOpal Liquidus 820 900 680 990 920 700 750 810 -- -- 580__________________________________________________________________________ A B C D E__________________________________________________________________________ Opacity Dense Dense Dense Dense Dense S.P. 726 775 806 839 876 Exp. 85.6 81.7 80.9 82.3 84.1 Na.sub.2 O Extraction 2.7 -- 2.8 -- -- Detergent 24 hrs A -- AA -- -- Rating 48 hrs A -- A -- -- 72 hrs A -- A -- -- 96 hrs A -- A -- -- Lowest Forming Temp. - Hand Pressing (°C.) 1250 -- 1300 -- -- Emulsion Liquidus 1150 1120 1150 1280 1180 Crystalline Opal Liquidus 580 570 620 690 680__________________________________________________________________________ *Loss of Gloss
A study of Table III in conjunction with Tables I and II immediately points up the criticality of composition control to secure glasses demonstrating the desired physical properties along with satisfactory melting and forming characteristics. Example C of Table II represents the most preferred composition in overall terms of forming behavior, chemical durability, and physical properties.
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This invention is directed to spontaneous opal glasses wherein Ba 2 F(PO 4 ) constitutes the predominant crystalline opal phase. The glasses exhibit softening points in excess of 710° C., excellent chemical durability, and consist essentially, in weight percent on the oxide basis, of 6-10% Na 2 O, 1-6% K 2 O, 4-11% BaO, 9-18% Al 2 O 3 , 50-70% SiO 2 , 3.5-7% P 2 O 5 , and 1-4% F.
| 2 |
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a black dye composition and a black ink composition and, more particularly, to a black dye composition and a black ink composition used for textile digital printing and suitable for ink-jet printing on cellulose fiber materials.
[0003] 2. Description of Related Art
[0004] Ink-jet printing has been applied in the textile industry for many years. The method of ink-jet printing can omit the manufacture of a screen to save the cost and time. More particularly, the required variation can be realized in a shorter time when designing various patterns.
[0005] In the view of application, the best properties of an ink composition are required for ink-jet printing, such as viscosity, stability, surface tension, and flow ability. In addition, resulting printed fabric has to exhibit better properties, such as color yield, fixation, stability of association between fibers and dyes, moisture fastness and so on.
[0006] An ink composition used for ink-jet printing comprises a dye that can dissolve or disperse in water or a liquid medium containing a water-soluble organic solvent. In addition, a surfactant can also be added into the ink composition to change the properties of the ink composition to meet with the requirement for textile ink-jet printing.
[0007] U.S. Pat. No. 6,015,454 discloses an ink composition comprising at least one reactive dye, and 1,2-propylene glycol or N-methyl-2-pyrrolidone. The ink composition disclosed by U.S. Pat. No. 6,015,454 improves the color depth and fastness properties of ink-jet printed fabric. However, the stability properties of storage and printing for long time are poor, and nozzle cloggage occurs at the same time.
[0008] U.S. Application No. 2003/0172840 discloses an ink composition comprising at least one reactive dye, sulfolane, and a buffer system. The ink composition disclosed by U.S. Application No. 2003/0172840 improves the stability of storage and nozzle cloggage. However, chlorine-resistant fastness, color depth, and solubility of dyes need to be improved.
[0009] Thereby, it is an important issue to provide a black dye composition used for the manufacture of a black ink composition for textile digital ink-jet printing, which exhibits the properties (such as improved light-fastness, chlorine-resistant fastness, color depth, solubility of dyes and so on).
SUMMARY OF THE INVENTION
[0010] The present invention provides a black dye composition and a black ink composition for textile digital ink-jet printing, which exhibits many improved properties for printing cellulose fibers and cellulosic blended fibers.
[0011] The black dye composition of the present invention comprises:
[0012] (a) at least one azo dye of the following formula (I),
[0000]
[0000] wherein R 1 is —SO 2 CH 2 CH 2 OSO 3 H, —SO 2 CH═CH 2 , or
[0000]
[0000] R 2 and R 3 each independently is —CH 3 , —OCH 3 , or H; and
[0013] (b) at least one azo dye of the following formula (II) or (III),
[0000]
[0000] wherein R 1 , R 2 , and R 3 are defined as above.
[0014] The black dye composition of the present invention can further comprise:
[0015] (c) at least one azo dye of the following formula (IV) or (V),
[0000]
[0000] wherein R 1 , R 2 , and R 3 are defined as above.
[0016] Examples of the azo dye of the formula (I) are
[0000]
[0017] Preferably, the azo dye of the formula (II) is the following formula (II-A) or (II-B).
[0000]
[0018] Examples of the azo dye of the formula (II) are
[0000]
[0019] Preferably, the azo dye of the formula (III) is the following formula (III-1).
[0000]
[0020] Examples of the azo dye of the formula (IV) are
[0000]
[0021] Preferably, the azo dye of the formula (V) is the following formula (V-1).
[0000]
[0022] The dyes of the present invention are represented in the form of free acid. However, in practice, they often exist as metallic salts or ammonium salts, and most likely alkaline metallic salts or ammonium salts.
[0023] The component ratio of the black dye composition of the present invention is not especially limited. If the black dye composition comprises component (a) and component (b), preferably, the content of component (a) is 50˜97% by weight, and the content of component (b) is 50˜3% by weight.
[0024] If the black dye composition comprises component (a), component (b), and component (c), preferably, the content of component (a) is 50˜94% by weight, the content of component (b) is 47˜3% by weight, and the content of component (c) is 3˜30% by weight.
[0025] The black dye composition of the present invention can be further used for the manufacture of a black ink composition.
[0026] The black ink composition of the present invention comprises:
[0027] (A) 5˜35% by weight of the aforementioned black dye composition, which can comprise the component (a) and component (b) or comprise the component (a), component (b), and component (c); and
[0028] (B) 5˜30% by weight of organic solvent selected form the group consisting of ethylene glycol, 1,3-butanediol, 2-methyl-2,4-pentanediol, 1,2-propanediol, 2-pyrrolidone, and N-methyl-2-pyrrolidone; and
[0029] 90˜35% by weight of water.
[0030] The black ink composition of the present invention used for textile digital ink-jet printing can further comprise component (C):
[0031] (C) 0.1˜5% by weight of a surfactant of the following formula (VI), such as Surfynol 465, Surfynol 485, Surfynol 420, and Surfynol 104 (sold by Air Products & Chemicals),
[0000]
[0000] wherein the sum of n and m is integer between 0 and 50. Preferably, the sum of n and m is integer between 0 and 20 and the content of the surfactant is 0.1˜3% by weight.
[0032] If necessary, other additives (such as microbicide or antifoam agent) can be added to the black ink composition of the present invention. Preferably, the additive are, for example, NUOSEPT ( sold by Nudex Inc., a division of Huls Americal), UCARCIDE (sold by Union Carbide), VANCIDE (sold by RT Vanderbikt Co.), and PROXEL XL2 (sold by ICI Americas). For the black ink composition, the content of the additives is 0.01˜1% by weight. For example, the black ink composition of the present invention used for textile digital ink-jet printing can further comprise component (D): microbicide. Preferably, the content of the microbicide is 0.01˜1% by weight.
[0033] Accordingly, the black ink component of the present invention exhibits the properties of excellent color depth, fixation, stability of storage, stability and accuracy of printing for long time, and improves the issue of nozzle cloggage.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1 shows the K/S curves of the black ink compositions of Examples 15, 23, 24, and Comparative Example 1, wherein “______” is the K/S curve of the black ink compositions of Example 15, “______-______” is the K/S curve of the black ink compositions of Example 24, “- - - ” is the K/S curve of the black ink compositions of Example 23, and “. . . ” is the K/S curve of the black ink compositions of Comparative Example 1.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0035] The dye compound of the formula (IV) can be synthesized by the following synthetic steps.
[0036] 1-aminobenzene-2-sulfonic acid-4-β-sulfatoethylsulfone is dissolved in ice acid-water, followed by the rapid addition of sodium nitrite to perform diazotization. Subsequently, 2-amono-5-hydroxynaphthalene-7-sulfonic acid is added to the reaction solution to perform coupling reaction.
[0037] Then, 1-aminobenze-2,5-dimethoxy-4-β-sulfatoethylsulfone is dissolved in ice acid-water, followed by the addition of sodium nitrite to perform diazotization. Subsequently, the compound afforded by the aforementioned coupling reaction is added to the reaction solution, the pH value of the reaction solution is adjusted to 5˜6, and the coupling reaction is performed in the temperature range of 10° C. to 15° C. to afford the compound of the formula (IV-1).
[0038] The black dye compound of the formula (II) can be synthesized by the following synthetic steps.
[0039] 1-aminobenzene-2-sulfonic acid-4-β-sulfatoethylsulfone is dissolved in ice acid-water, followed by the rapid addition of sodium nitrite to perform diazotization. Subsequently, 3,5-diaminobenzoic acid powders are added to the reaction solution to perform coupling reaction.
[0040] Then, 1-aminobenze-4-β-sulfatoethylsulfone is dissolved in ice acid-water, followed by the addition of sodium nitrite to perform diazotization. Subsequently, the compound afforded by the aforementioned coupling reaction is added to the reaction solution, the pH value of the reaction solution is adjusted to 3.5˜5.0, and the coupling reaction is performed in the temperature range of 5° C. to 15° C. to afford the compound of the formula (II-1).
[0041] The preparation of the compounds of the formula (I), (III), and (V) is described in Taiwan Patent No. TW 323299, and Japanese Patent laid-open No. 45-40182.
[0042] The water-soluble reactive dyes in the black ink composition of the present invention can be the aforementioned dyes or the alkali metal salts thereof used alone or in a mixture. Preferably, the salt amount existing in the reactive dyes should be low. It means that with respect to the total weight of the reactive dyes of the present invention, the total salt amount existing in the reactive dyes is less than 0.5% by weight. The reactive dyes with the high amount of salts afforded from the preparation and/or the following addition of diluents can be proceeded with the procedure of salt exclusion, such as thin-film process (e.g. super filtration, reverse osmosis, or osmosis).
[0043] With respect to the total weight of the black ink composition of the present invention, the black ink composition of the present invention comprises 5˜35% by weight of reactive dyes, 35˜90% by weight of water, and 5˜30% by weight of organic solvent.
[0044] Preferably, the black ink composition of the present invention comprises 10˜30% by weight of reactive dyes, 40˜85% by weight of water, and 5˜30% by weight of organic solvent.
[0045] The content of an organic solvent in the black ink composition relates to the wet-keeping property of nozzles, the stability of printing and storage. The content of the organic solvent is 5˜30% by weight. Preferably, the content of the organic solvent is 10˜20% by weight.
[0046] The black ink composition of the present invention can be prepared by the conventional method, mixing all components in water of required amount.
[0047] The black ink compositions of the present invention can dye cellulose fiber materials. Examples of cellulose fiber materials are natural cellulose fibers (such as cotton, linen, and hemp) and regenerated cellulose fibers. The black ink composition of the present invention is also suitable for dyeing or printing fibers, which contain hydroxyl groups and are contained in blended fabrics.
[0048] The black ink composition of the present invention can be fixed on the fiber materials by digital ink-jet printing and, more particularly, by piezoelectric digital ink-jet printing.
[0049] The black ink component of the present invention exhibits the properties of excellent color depth, fixation, stability of storage, stability and accuracy of printing for long time, and improves the issue of nozzle cloggage.
[0050] According to the black ink composition of the present invention, the resulting printed fabric exhibits the excellent properties, such as stable binding between fibers and dyes in the acid or basic condition, excellent light fastness, wet fastness (e.g. wash fastness, water fastness, seawater fastness, cross-dyeing fastness, and moisture fastness), chlorine-resistant fastness, pleating fastness, ironing fastness, and rubbing fastness, as well distinct outline and excellent color depth.
[0051] The examples sited below should not be taken as a limit to the scope of the invention. Wherein the compounds are represented in the form of free acid. However, in practice, they often exist as metallic salts or ammonium salts, and most likely alkaline metallic salts or ammonium salts. Unless otherwise stated, the parts and percent used in the following examples are based on weight, and the temperature is in degree Celsius (° C.).
PREPARATION EXAMPLE 1
[0052] 36.1 parts of 1-aminobenzene-2-sulfonic acid-4-β-sulfatoethylsulfone is dissolved in 1000 parts of ice water, followed by the addition of 24 parts of 32% HCl aqueous solution and then 7.0 parts of sodium nitrite aqueous solution to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, 23.9 parts of 2-amino-5-hydroxy-naphthalene-7-sulfonic acid is added to the reaction solution to perform coupling reaction. Finally, the compound of the following formula (1) is afforded by NaCl salting-out and then filtration.
[0000]
[0053] 34.1 parts of 1-aminobenze-2,5-dimethoxy-4-β-sulfatoethylsulfone is dissolved in 1000 parts of ice water, followed by the addition of 24 parts of 32% HCl aqueous solution and then 7.0 parts of sodium nitrite to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, the compound (1) afforded by the aforementioned coupling reaction is added therein, the pH value of the reaction solution is adjusted to 5˜6 by sodium carbonate, and the coupling reaction is performed in the temperature range of 10° C. to 15° C. Finally, the compound of the following formula (IV-1) is afforded by NaCl salting-out and then filtration.
[0000]
PREPARATION EXAMPLE 2
[0054] 32.5 parts of 1-aminobenzene-2-methoxy-5-methyl-4-β-sulfatoethylsulfone is dissolved in 1000 parts of ice water, followed by the addition of 24 parts of 32% HCl aqueous solution and then 7.0 parts of sodium nitrite aqueous solution to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, the compound (1) afforded by the aforementioned coupling reaction is added therein, the pH value of the reaction solution is adjusted to 5˜6 by sodium carbonate, and the coupling reaction is performed in the temperature range of 10° C. to 15° C. Finally, the compound of the following formula (IV-2) is afforded by NaCl salting-out and then filtration.
[0000]
PREPARATION EXAMPLE 3
[0055] 28.1 parts of 1-aminobenzene-4-β-sulfatoethylsulfone is dissolved in 1000 parts of ice water, followed by the addition of 24 parts of 32% HCl aqueous solution and then 7.0 parts of sodium nitrite aqueous solution to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, 23.9 parts of 2-amino-5-hydroxy-naphthalene-7-sulfonic acid is added to the reaction solution to perform coupling reaction. Finally, the compound of the following formula (2) is afforded by NaCl salting-out and then filtration.
[0000]
[0056] 34.1 parts of 1-aminobenzene-2,5-dimethoxy -4-β-sulfatoethylsulfone is dissolved in 1000 parts of ice water, followed by the addition of 24 parts of 32% HCl aqueous solution and then 7.0 parts of sodium nitrite aqueous solution to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, the compound (2) afforded by the aforementioned coupling reaction is added therein, the pH value of the reaction solution is adjusted to 5˜6 by sodium carbonate, and the coupling reaction is performed in the temperature range of 10° C. to 15° C. Finally, the compound of the following formula (IV-3) is afforded by NaCl salting-out and then filtration.
[0000]
PREPARATION EXAMPLE 4
[0057] 36.1 parts of 1-aminobenzene-2-sulfonic acid-4-β-sulfatoethylsulfone is dissolved in 1000 parts of ice water, followed by the addition of 24 parts of 32% HCl aqueous solution and then 7.0 parts of sodium nitrite aqueous solution to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, 15.2 parts of 3,5-diaminobenzoic acid powder is added to the reaction solution to perform coupling reaction. Finally, the compound of the following formula (3) is afforded by NaCl salting-out and then filtration.
[0000]
[0058] 28.1 parts of 1-aminobenzene-4-β-sulfatoethylsulfone is dissolved in 200 parts of ice water, followed by the addition of 24 parts of 32% HCl aqueous solution and then 7.0 parts of sodium nitrite aqueous solution to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, the compound (3) afforded by the aforementioned coupling reaction is added therein, the pH value of the reaction solution is adjusted to 3.5˜5.0 by sodium bicarbonate, and the coupling reaction is performed in the temperature range of 5° C. to 15° C. Finally, the compound of the following formula (II-1) is afforded by NaCl salting-out and then filtration.
[0000]
PREPARATION EXAMPLE 5
[0059] 32.5 parts of 1-aminobenzene-2-methoxy-5-methyl-4-β-sulfatoethylsulfone is dissolved in 200 parts of ice water, followed by the addition of 24 parts of 32% HCl aqueous solution and then 7.0 parts of sodium nitrite aqueous solution to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, the compound (3) afforded by the aforementioned coupling reaction is added therein, the pH value of the reaction solution is adjusted to 3.5˜6.0 by sodium bicarbonate, and the coupling reaction is performed in the temperature range of 5° C. to 15° C. Finally, the compound of the following formula (II-5) is afforded by NaCl salting-out and then filtration.
[0000]
PREPARATION EXAMPLE 6
[0060] 72.2 parts of 1-aminobenzene-2-sulfonic acid-4-β-sulfatoethylsulfone is dissolved in 2000 parts of ice water, followed by the addition of 48 parts of 32% HCl aqueous solution and then 14.0 parts of sodium nitrite aqueous solution to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, 10.8 parts of phenylenediamine powder is added therein. The reaction solution is stirred for 3 hours, and then the pH value thereof is adjusted to 3.5˜6.0 by sodium bicarbonate. The reaction solution is stirred in the temperature range of 5° C. to 15° C. to perform coupling reaction. Finally, the compound of the following formula (II-2) is afforded by NaCl salting-out and then filtration.
[0000]
PREPARATION EXAMPLE 7
[0061] 36.1 parts of 1-aminobenzene-2-sulfonic acid-4-β-sulfatoethylsulfone is dissolved in 1000 parts of ice water, followed by the addition of 24 parts of 32% HCl aqueous solution and then 7.0 parts of sodium nitrite aqueous solution to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, 10.8 parts of phenylenediamine powder is added therein to perform coupling reaction so as to afford the compound of the following formula (4).
[0000]
[0062] 28.1 parts of 1-aminobenzene-4-β-sulfatoethylsulfone is dissolved in 200 parts of ice water, followed by the addition of 24 parts of 32% HCl aqueous solution and then 7.0 parts of sodium nitrite aqueous solution to perform diazotization in the temperature range of 0° C. to 5° C. Subsequently, the compound (4) afforded by the aforementioned coupling reaction is added therein, the pH value of the reaction solution is adjusted to 3.5˜5.0 by sodium bicarbonate, and the coupling reaction is performed in the temperature of 5° C. to 15° C. Finally, the compound of the following formula (II-7) is afforded by NaCl salting-out and then filtration.
[0000]
EXAMPLE 1
Preparation of Black Dye Composition
[0063] 83.4 parts of (I-1) dye, 11.1 parts of (V-1) dye, and 5.5 parts of (III-1) dye are mixed, water is added to form 1000 parts of solution, and the pH value of the solution is adjusted to 4˜6. Finally, a black dye composition is afforded by reverse osmosis salt exclusion and dryness.
EXAMPLE 2
Preparation of Black Dye Composition
[0064] 44.4 parts of (I-1) dye, 39.0 parts of (I-4) dye, 11.1 parts of (V-1) dye, and 5.5 parts of (III-1) dye are mixed, water is added to form 1000 parts of solution, and the pH value of the solution is adjusted to 4˜6. Finally, a black dye composition is afforded by reverse osmosis salt exclusion and dryness.
EXAMPLE 3˜14
[0065] The black dye compositions of the present invention are prepared by repeating the steps of Example 1, but changing the components and the component ratio.
[0066] The components and the component ratio of the black dye compositions of Examples 3 to 8 are shown in the following Table 1. The components and the component ratio of the black dye compositions of Examples 9 to 14 are shown in the following Table 2.
[0000]
TABLE 1
Component and Component Ratio
Example
(I-1) Dye
(I-4) Dye
(I-6) Dye
(V-1) Dye
(III-1) Dye
3
44.4%
0%
39.0%
11.1%
5.5%
4
55.5%
27.9%
0%
11.1%
5.5%
5
55.5%
0%
27.9%
11.1%
5.5%
6
27.7%
55.7%
0%
11.1%
5.5%
7
27.7%
0%
55.7%
11.1%
5.5%
8
44.4%
16.6%
22.4%
11.1%
5.5%
[0000]
TABLE 2
Component and Component Ratio
Example
(I-1)Dye
(II-A)Dye
(II-B) Dye
(IV-1)Dye
9
83.3%
16.7%
0%
0%
10
83.3%
0%
11.1%
5.6%
11
94.4%
5.6%
0%
0%
12
88.8%
0%
5.6%
5.6%
13
58.8%
0%
29.4%
11.8%
14
83.3%
5.6%
5.6%
5.5%
EXAMPLE 15
Preparation of Black Ink Composition
[0067] (A) 18.0 parts of the black dye composition of Example 1; (B) 10.0 parts of 1,3-butanediol, and 5.0 parts of 2-pyrrolidone; (C) 0.5 parts of nonionic surfactant of Surfynol 465; and (D) 0.2 parts of microbicide of Proxel XL2 are mixed; and water is added to form 100 parts of solution. The solution is stirred at room temperature to afford the black ink composition.
EXAMPLE 16
Preparation of Black Ink Composition
[0068] (A) 18.0 parts of the black dye composition of Example 2; (B) 10.0 parts of 1,3-butanediol, and 5.0 parts of 2-pyrrolidone; (C) 0.5 parts of nonionic surfactant of Surfynol 465; and (D) 0.2 parts of microbicide of Proxel XL2 are mixed; and water is added to form 100 parts of solution. The solution is stirred at room temperature to afford the black ink composition.
EXAMPLE 17
Preparation of Black Ink Composition
[0069] (A) 18.0 parts of the black dye composition of Example 3; (B) 10.0 parts of 1,3-butanediol, and 5.0 parts of 2-pyrrolidone; (C) 0.5 parts of nonionic surfactant of Surfynol 465; and (D) 0.2 parts of microbicide of Proxel XL2 are mixed; and water is added to form 100 parts of solution. The solution is stirred at room temperature to afford the black ink composition.
EXAMPLE 18-28
[0070] The black ink compositions of the present invention are prepared by repeating the steps of Example 17, but changing the components and the component ratio.
[0071] The components and the component ratio of the black ink compositions of Examples 18 to 28 are shown in the following Table 3.
[0000]
TABLE 3
Component and Component Ratio
Com-
Com-
Com-
ponent
ponent
ponent
(A)
(C)
(D)
18 Parts of
Component (B)
Parts of
Parts of
Ex-
Black Dye
Parts of 1,3-
Parts of 2-
Surfynol
Proxel
ample
Composition
butanediol
pyrrolidone
465
XL2
18
Example 4
10
5
0.5
0.2
19
Example 5
5
10
1
0.2
20
Example 6
5
15
1.5
0.2
21
Example 7
10
5
0.3
0.2
22
Example 8
10
5
0.5
0.2
23
Example 9
10
5
0.5
0.2
24
Example 10
5
10
1
0.2
25
Example 11
5
15
1.5
0.2
26
Example 12
10
5
0.3
0.2
27
Example 13
10
5
0.5
0.2
28
Example 14
10
5
0.5
0.2
EXAMPLE 29-31
[0072] The black ink compositions of the present invention are prepared by repeating the steps of Example 15, but changing the component (B) and the component ratio thereof.
[0073] The components and the component ratio of the black ink compositions of Examples 29 to 31 are shown in the following Table 4.
[0000]
TABLE 4
Component and Component Ratio
Com-
ponent
Component
(A)
(B)
Black Dye
Parts of
Ex-
Com-
Parts of
2-methyl-
am-
position
1,3-
Parts of 2-
2,4-
Parts of 1,2-
ple
(18 parts)
butanediol
pyrrolidone
pentanediol
propanediol
29
Example 1
5
10
0
0
30
Example 1
0
10
5
0
31
Example 1
0
0
5
10
COMPARATIVE EXAMPLE 1
Preparation of Black Ink Composition
[0074] 18.0 parts of Reactive Black 5, 10.0 parts of 1,3-butanediol, 5.0 parts of 2-pyrrolidone, 0.5 parts of nonionic surfactant of Surfynol 465, and 0.2 parts of microbicide of Proxel XL2 are mixed, and water is added to form 100 parts of solution. The solution is stirred at room temperature to afford the black ink composition.
COMPARATIVE EXAMPLE 2
Preparation of Black Ink Composition
[0075] 18.0 parts of Reactive Black 8, 10.0 parts of 1,3-butanediol, 5.0 parts of 2-pyrrolidone, 0.5 parts of nonionic surfactant of Surfynol 465, and 0.2 parts of microbicide of Proxel XL2 are mixed, and water is added to form 100 parts of solution. The solution is stirred at room temperature to afford the black ink composition
Test of Printing
Preliminary Treatment
[0076] Urea 100 parts, reduction retarding agent 10 parts, sodium bicarbonate 20 parts, sodium alginate 60 parts, and warm water 810 parts (1000 parts in total) are stirred in a vessel to give a completely homogeneous printing paste. The materials of the used fabric can be fibers or regenerated fibers. The fabric used in the Example is 3/1 twill. Before printing, the fabric is padded with the aforementioned printing paste (PICK-UP 70%) by a roller, and then dried by 100° C. steam.
Printing, Fixing, and Post Treatment
[0077] The fabric is printed by the nozzles of a piezo printer (Mimaki JV-22).
[0078] The black ink compositions of Example 15 to 31, Comparative Example 1, and Comparative Example 2 are individually installed in the piezo printer. The aforementioned fabric obtained by preliminary treatment is printed and then pre-dried in the condition of 50° C.×2 min, followed by fixation for 8˜15 min by 102-110° C. saturated steam. Subsequently, the fabric is washed by 100° C. water and water containing washing reagent, and then dried.
Result of Dyeing Test:
[0079] The colored fabric obtained through the aforementioned process for printing with the ink composition of the example, wash with water, and then dryness exhibits the excellent dyeing properties, as shown in Table 5.
[0000]
TABLE 5
Result of Dyeing Test
The Level of
Black Ink
Solubility of
Chlorine-Resistant
Relative Color
Composition
Dyes
Fastness
Depth
Example 15
>150
g/L
3-4
114%
Example 16
>150
g/L
3-4
110%
Example 17
>150
g/L
3-4
107%
Example 18~22
>150
g/L
3-4
>105%
Example 23
>150
g/L
3-4
118%
Example 24
>150
g/L
4-5
115%
Example 25~28
>150
g/L
3-4
>110%
Example 29~31
>150
g/L
3-4
>110%
Comparative
About 150
g/L
2
AS 100%
Example 1
Comparative
About 80
g/L
3-4
<80%
Example 2
[0080] According to Table 5, it is found that the black ink composition of the present invention exhibits the property of excellent solubility of dyes (>150 g/L), which is suitable for preparing a black ink composition with high concentration for textile digital printing. In addition, the level of chlorine-resistant fastness of the black ink composition is 1-2 higher than that of comparative example 1. Most importantly, the relative color depth of the black ink composition of the present invention is 10% higher than that of comparative example 1. In comparison to comparative example 2, the build-up of the black ink composition of the present invention is obviously better
[0081] Please refer to FIG. 1 . K/S curves of the black ink compositions of Example 15, Example 23, Example 24, and Comparative Example 1 are shown in FIG. 1 . According to the K/S curves, it is found that the absorption of Comparative Example 1 at single wavelength is too high and the color is bluish (especially in grey-level), resulting in the pure black appearance cannot be achieved. Thereby, the black ink composition of Comparative Example 1 is not popular in market. The black ink compositions of Examples 15, 23, and 24 exhibit more full-range wavelength absorption and will be more darkness.
[0082] According to the results of various tests, the black ink composition obtained from the black dye composition of the present invention exhibits excellent properties of color depth and chlorine-resistant fastness in textile digital printing. The color gamut of the colored black fabric can be from greenishness to reddishness. Thereby, the color gamut of the digital printed black fabric is broad, and the build-up thereof is excellent.
[0083] Although the present invention has been explained in relation to its preferred embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the scope of the invention as hereinafter claimed.
|
The present invention relates to a black dye composition, comprising: (a) at least one azo dye of the following formula (I),
(b) at least one azo dye of the following formula (II) or (III),
wherein R 1 , R 2 , and R 3 are defined the same as the specification. The present invention also relates to a black ink composition afforded from the aforementioned black dye composition. The black ink composition of the present invention for textile digital printing exhibits the properties of excellent color depth, fixation, stability of storage, stability and accuracy of printing for long time, and improves the issue of nozzle cloggage.
| 2 |
THE FIELD OF THE INVENTION
[0001] The present invention relates to an axle-lifting device, a method for lifting an axle and axle assemblies which may be used in vehicles.
BACKGROUND INFORMATION
[0002] The axles and axle assemblies of vehicles are designed for a predetermined load. In vehicles having a very high ratio of empty/loaded, the problem encountered during “empty” or “partially loaded” load states is that the actual load on the axles and assemblies is much lower than the design load. This may lead to disproportionate wear on the tires and brake pads, among other things, in relation to the use of the axle, namely the load carried.
[0003] This problem is usually solved by an axle-lifting device, for example, an axle lift, which lifts the axle and parts of the assembly in the “empty” and “partially loaded” states and thus solves the aforementioned problem. The axle lift is a separate component, which has only the purpose of lifting the axle. In more recent modular approaches, an axle lift may also be retrofitted.
SUMMARY OF THE INVENTION
[0004] An object of the exemplary embodiments and/or exemplary methods of the present invention is to create an improved axle-lifting device, an improved method for lifting an axle and an improved axle assembly.
[0005] This object is achieved by an axle-lifting device as recited herein, a method for lifting an axle as recited herein, and an axle assembly as recited herein.
[0006] The exemplary embodiments and/or exemplary methods of the present invention is based on the idea that axle components or axle assembly components, which are usually present, may be used to lift an axle by slightly modifying the axle components or axle assembly components which are usually present.
[0007] According to the exemplary embodiments and/or exemplary methods of the present invention, all the components which are capable of directly or indirectly generating a force component in the axle-lifting direction according to their task may be considered for this purpose. Thus, a force required to lift the axle may be generated by a force-generating component, which is already present on the vehicle and is also used for other purposes.
[0008] It is advantageously possible for the components, which are used for lifting the axle according to the present invention, to continue to fulfill the task for which they were originally provided. Thus only a few additional components or none at all are necessary for lifting the axle.
[0009] The exemplary embodiments and/or exemplary methods of the present invention creates an axle-lifting device for lifting an axle of a vehicle, having the following features:
[0010] A function mechanism for generating a force component in an axle-lifting direction, the function mechanism being designed to generate a first force component for providing a first functionality and to generate a second force component to lift the axle in the axle-lifting direction.
[0011] According to one embodiment, the function mechanism may be a shock absorber, which is already present. Shock absorbers are usually operated with a fluid and dissipate the energy introduced due to bumps in the road by converting it into heat at a throttle point. Forces are thus generated in the spring compression and spring deflection directions. A set-up and activation of the shock absorber according to the present invention makes it possible to use this shock absorber force to lift the axle. In this way, a component which already exists may be utilized in multiple ways. This allows a separate axle lift to be omitted.
[0012] The present invention also creates a method for lifting an axle of a vehicle, having the following steps:
[0013] Providing a function mechanism for generating a force component in an axle-lifting direction, the function mechanism being designed to generate a first force component to provide a first functionality and to generate a second force component in the axle-lifting direction to lift the axle; and
[0014] Providing a control signal to the function mechanism to generate the second force component.
[0015] The exemplary embodiments and/or exemplary methods of the present invention also creates an axle assembly having the following features:
[0016] A trestle which may be connected to a chassis;
[0017] A suspension arm for accommodating an axle, the suspension arm being movably connected to the trestle; and
[0018] An axle-lifting device as described herein, the axle-lifting device being connected to the suspension arm.
[0019] Exemplary embodiments of the present invention are explained in greater detail below with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 shows a representation of an assembly having an axle-lifting device according to the present invention.
[0021] FIG. 2 shows a representation of another assembly having an axle-lifting device according to the present invention.
DETAILED DESCRIPTION
[0022] In the following description of the exemplary embodiments of the present invention, the same or similar reference numerals are used for the similar elements represented in the various drawings, so a repeat description of these elements is omitted here.
[0023] FIG. 1 shows an axle assembly having an axle-lifting device according to one exemplary embodiment of the present invention. The axle assembly may be connected to a chassis 102 of a vehicle and has a trestle 104 and a suspension arm 106 . Trestle 104 is connected to chassis 102 . One end of suspension arm 106 is rotatably mounted on trestle 104 . The axle assembly may also have a bellows 108 . Bellows 108 is connected to chassis 102 and is designed to absorb a movement of suspension arm 106 in the direction of chassis 102 . For this purpose, bellows 108 may be situated on one end of suspension arm 106 opposite trestle 104 . Suspension arm 106 is designed to accommodate an axle 110 .
[0024] The axle assembly has an axle-lifting device having a function mechanism 122 . According to this exemplary embodiment, the function mechanism is designed as a shock absorber 122 . Shock absorber 122 has a separating piston 124 . Furthermore, a fluid is situated within shock absorber 122 , so that movement of the separating piston 124 may be dampened. Shock absorber 122 is designed to generate at least one force component in an axle-lifting direction H, which points in the direction of chassis 102 . Furthermore, shock absorber 122 may be designed to generate a force component in the opposite direction.
[0025] The force component in the axle-lifting direction may cause the lifting of axle 110 or prevent or retard the lowering of axle 110 . The force component in the opposite direction may cause a lowering of axle 110 or prevent or retard a lifting of axle 110 . Shock absorber 122 may be designed to use the force component in axle-lifting direction H for both lifting of axle 110 and for at least one additional functionality. According to this exemplary embodiment, the additional functionality may include damping or suspension of axle 110 .
[0026] Due to a predetermined pressure distribution and/or fluid quantity distribution within shock absorber 122 , a resting position of the separating piston and thus a height level of axle 110 may be set. A permanent change in the predetermined pressure distribution and/or fluid quantity distribution may cause a displacement of the resting position of separating piston 124 . The force component in axle-lifting direction H may be generated due to the displacement of the resting position. A force component may be generated due to pressure acting on space 126 of shock absorber 122 in particular, resulting in the lifting of axle 110 . Shock absorber 122 may have a valve for applying pressure to space 126 . Alternatively, the valve as well as the necessary force-generating component for the fluid quantity/fluid pressure may also be mounted outside of component 122 . A component which also provides fluidic volumes for other purposes, for example, a manually operable hydraulic pump, which is used to lift the driver's cab (in a truck) or to lift a roof panel (on a trailer) may also be used as the force generating component.
[0027] The application of pressure to space 126 may take place in response to a supplied control signal. The control signal may be generated by a control device connected to shock absorber 122 . Since the load state is proportional to the fluid pressure in fluid suspensions, there may be direct control of the axle-lifting device.
[0028] The axle assembly shown in FIG. 1 may be a pneumatic suspension of a truck, a truck trailer or a truck semi-trailer. According to this exemplary embodiment, shock absorber 122 is situated between trestle 104 and suspension arm 106 . Shock absorber 122 is connected to trestle 104 in the vicinity of chassis 102 on the one hand, while on the other hand, it is connected to suspension arm 106 in the vicinity of axle 110 .
[0029] FIG. 2 shows an axle assembly having an axle-lifting device according to another exemplary embodiment of the present invention. The design of the axle assembly corresponds to the design shown in FIG. 1 . According to this exemplary embodiment, function mechanism 122 is designed as a bellows. Bellows 122 has a separating piston 124 and is provided for damping of axle 110 or chassis 102 . The damping is thus performed with a compressible fluid, in particular using the same medium, which is also used for the suspension. According to the exemplary embodiments and/or exemplary methods of the present invention, bellows 122 may additionally be used for lifting axle 110 . According to the exemplary embodiment illustrated in FIG. 1 , applying pressure to space 126 results in axle 110 being lifted.
[0030] The assembly shown in FIG. 2 may be a pneumatic suspension of a truck, a truck trailer or a truck semi-trailer having a pneumatic suspension shock absorber. According to this exemplary embodiment, bellows 122 is situated between chassis 102 and suspension arm 106 . Bellows 122 is connected on the one hand to chassis 102 and on the other hand to suspension arm 106 at one end, which is opposite trestle 104 .
[0031] The exemplary embodiments described here are selected only as examples and may be combined with one another. Instead of the shock absorber described here, the axle-lifting device according to the present invention may also be based on any other spring component, shock absorber component or other component, which may be used as an axle-lifting device in addition to its primary function.
The List of Reference Numerals is as Follows:
[0032] 102 chassis
[0033] 104 trestle
[0034] 106 suspension arm
[0035] 108 bellows
[0036] 110 axle
[0037] 122 shock absorber
[0038] 124 separating piston
[0039] 126 pressure space
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An axle-lifting device for lifting an axle of a vehicle. The axle-lifting device includes a function mechanism for generating a force component in an axle-lifting direction. The function mechanism is configured to generate a first force component for providing a first functionality and a second force component for lifting the axle in the axle-lifting direction.
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BACKGROUND
[0001] The invention relates generally to welding systems, and more particularly to improved grounding connections for pipe welding and other welding applications.
[0002] An essential part of welding practice is properly grounding the workpiece. This ensures that the workpiece is at or very near the same potential as a ground terminal of a power supply so that a circuit can be completed through the workpiece to establish and maintain a welding arc. Consequently, a primary source of compromised welds is faulty ground connection to the workpiece. Traditionally, grounding is done through a work clamp that clamps onto the workpiece (or a fixture to which the workpiece is mounted) and which is grounded through a cable extending back to a welding power supply. However, work clamps are only suitable for workpieces of limited size and shape, such as those with straight or flat sides and of manageable size. However, using work clamps is unfeasible for pipe welding, or for other unwieldy shapes due to limited contact areas (e.g., where two joints of pipe are closely positioned end-to-end). Unfortunately, commonly used grounding techniques for pipe welding are to insert a grounding device into the gap between the two pipe joints or to place a grounding device on top of the two pipe joints, often being secured only through gravity. These grounding devices may just be pieces or blocks of conductive material, most of which are not specifically designed for the function of creating a good ground connection. The existing grounding techniques establish fragile contact angles that only touch a small surface of the workpiece. These weak connections result in a higher level of resistance as current is restricted, which can weaken the integrity of the weld and cause defects.
[0003] Additionally, the existing grounding techniques do not include a convenient means of measuring critical parameters such as current, voltage, and resistance, which can be used to verify an acceptable connection. This is an important function because the point of grounding contact on the workpiece may not always provide a sufficiently conductive surface. It is not uncommon for the workpiece to be corroded or soiled at the point of contact with the ground connection, preventing a solid ground connection. For example, there may be rust or other nonconductive debris between the conductive material of the workpiece and the grounding device. The result is a faulty or high resistance ground connection, potentially compromising the quality of the weld. Without a means of measuring and indicating ground connection quality, the operator has no knowledge of the poor connection and therefore may continue to weld with a faulty ground connection. A lack of feedback makes it difficult or impossible to detect and correct a poor ground connection. This is especially problematic in advanced process equipment as the current flow is precisely controlled to achieve optimal results.
[0004] There is a need for an improved grounding device that is capable of establishing a robust grounding connection as well as a means to verify that connection.
BRIEF DESCRIPTION
[0005] The present disclosure summarizes a newly developed welding ground connection system and method that fulfills these needs. The system involves a grounding device with which the workpiece is grounded via two conductive prongs with a centertap ground lead.
[0006] In accordance with one aspect of the present disclosure, a welding ground connection system and method make use of prongs that may be forced into intimate contact with one or more workpieces, and which also function as sensor leads. The prongs are coupled to an electronic circuit capable of having a user interface, taking characteristic measurements, outputting indications, and any combination of these, as well as other functions that may be desired.
[0007] In accordance with further aspects of the present disclosure, a grounding system body is secured to the workpiece by a magnet, though it can also by secured through other means of fastening the grounding system to the workpiece. A two pronged connection is created, which is ensured by the securely fastened body, significantly increasing the quality of the ground connection in comparison to existing solutions. Furthermore, the present disclosure discloses a method for grounding a workpiece while simultaneously taking and outputting measurements indicative of the quality of the ground.
DRAWINGS
[0008] These and other features, aspects, and advantages of the present invention will become better understood when the following detailed description is read with reference to the accompanying drawings in which like characters represent like parts throughout the drawings, wherein:
[0009] FIG. 1 is a diagrammatical representation of an exemplary welding system utilizing aspects of the disclosed welding ground connection system;
[0010] FIG. 2 is a detailed side view of the disclosed welding ground connection system for use with the welding system;
[0011] FIG. 3 is a detailed top view of the disclosed welding ground connection system for use with the welding system; and
[0012] FIG. 4 is a diagrammatical representation of the electronic circuitry of the disclosed welding ground connection system.
DETAILED DESCRIPTION
[0013] FIG. 1 illustrates an exemplary welding system 10 utilizing the disclosed welding ground connection system. The system 10 is designed to produce a weld 12 on a workpiece 14 . The system includes a power supply 16 that will typically be coupled to a gas source 18 and to a power source 20 , such as the power grid, although generators, engine-driven power packs, batteries, and so forth may all serve as power sources, particularly in more remote welding locations. A wire feeder 22 is coupled to the power supply 16 and supplies welding wire, shielding gas from the gas source, and welding power from the power supply to a welding gun 24 . In the illustrated embodiment, the power supply 16 will include power conversion circuitry 26 coupled to control circuitry 28 that regulates operation of the power conversion circuitry to produce power output suitable for the welding operation. The power supply may be designed and programmed to produce output power in accordance with a number of processes, welding regimes, and so forth, including constant current processes, constant voltage processes, pulsed processes short circuit transfer processes, and so forth. The power supply may also include valving 32 for regulating the flow of shielding gas from the gas source 18 . In the presently contemplated embodiment, an operator interface 30 allows a welding operator to alter both the welding process and the process settings. The power supply 16 also provides a ground terminal for a ground connection 42 of the grounding assembly 44 .
[0014] It should be noted that, while throughout the present discussion reference is made to a “ground” connection, this term should be understood generally to include a work connection at any desired potential. As will be appreciated by those skilled in the art, welding processes may call for positive or negative designations for the electrode and workpiece, although in all processes intended to be used with the present grounding techniques, a workpiece connection will be made, and advantageously with the systems and methods described.
[0015] The wire feeder 22 typically includes control circuitry 34 , which regulates the feed of welding wire from a spool 36 . The spool 36 contains welding wire, which serves as the electrode for the welding process and is advanced into the torch 24 by a drive assembly 38 . Welding wire, gas, and power are provided to the torch 24 via a weld cable 40 .
[0016] FIG. 2 and FIG. 3 show an exemplary grounding assembly 44 in relation to the workpiece in this embodiment. In the illustrated embodiment, the workpiece comprises two end-to-end positioned joints of pipe forming a first side 46 and a second side 48 separated by a gap 50 wherein a weld is to be formed. Typically, a gap 50 is left between the first side 46 and the second side 48 to allow full penetration of welding material, though a gap 50 is not necessary in order to use the grounding assembly 44 . The joint 12 may be configured in many different ways, with the ends of side 46 and side 48 having different configurations, including but not limited to a bevel as shown in FIG. 2 .
[0017] In the illustrated embodiment, the grounding assembly 44 comprises a body 52 , a non-conductive extension 54 , and prongs 56 , with the non-conductive extension 54 forming a downward arching shape and making contact with the workpiece 14 at a rear bearing 58 . The non-conductive extension 54 can be made of non-conductive materials of various compositions, and can be configured in many different forms as needed. The purpose of the non-conductive extension 54 is to stabilize the grounding assembly 44 about the workpiece 14 . Though the present embodiment illustrates the non-conductive extension 54 as having a long rectangular shape extending away from the prongs 56 in a downward arching configuration, it could have a number of different shapes and sizes and be oriented about the workpiece 14 in different ways. Utilizing the non-conductive extension 54 is one means of stabilizing the grounding assembly 44 about the workpiece 14 among others. There may be some embodiments where the nonconductive extension 54 is not used, but the prongs or contact structure is urged into engagement with workpiece by other means (e.g., a strap, a weight, etc.).
[0018] In the present embodiment, the grounding assembly 44 includes a compression assembly 60 , which compromises a magnet 62 , an adjustment assembly 64 , and a knob 66 , wherein the knob 66 is coupled to the adjustment assembly 64 , and the adjustment assembly 64 is coupled to the magnet 62 on the opposing end as more effectively illustrated in FIG. 2 . The magnet 62 is generally in stable magnetic contact with the surface of the workpiece 14 . The purpose of the compression assembly 60 is to secure the grounding assembly onto the workpiece 14 , specifically to ensure that the grounding assembly 44 is in robust conductive contact with the workpiece. The purpose of the adjustment assembly 64 is to raise, lower, or otherwise move the grounding assembly 44 with respect to the workpiece 14 so that the grounding assembly 44 is properly secured to the workpiece and in reliable electrical contact with the workpiece. In this embodiment, the compression assembly 60 is generally perpendicularly integrated into the body 52 as illustrated in FIG. 2 . The compression assembly 60 and the body 52 are generally fixed at their intersection. Specifically, the adjustment assembly 64 may contain threads such that the body 52 may be pulled displaced by the threads as the knob 66 is turned, moving the body either up or down the adjustment assembly, effectively determining the vertical location of the body 52 and the contact force of the grounding assembly 44 on the workpiece 14 (the entire assembly acting as a beam that exerts an increased contact force on the workpiece as the body is moved downwardly). As noted above, while the compression assembly 60 in this embodiment utilizes a magnet 62 and knob 66 mechanism, other means of attaching or holding the grounding assembly 44 in place relative to the workpiece 14 may be used in some other embodiments. These include but are not limited to other supports, clamps, wraps, human operators, external means of support, and so forth. The present configuration, including the compression assembly 60 and non-conductive extension 54 , is one embodiment of many different reasonable configurations that preserve the essence of the present invention.
[0019] As illustrated in FIG. 2 and the present embodiment, the prongs 56 are coupled to the body 52 of the grounding assembly 44 , and comprise tips 68 as shown. The prongs can be configured in various forms, including a wide range of shapes and sizes. The prongs 56 may be a separate part attached to the body 52 through various attachment methods, or they may be manufactured as one piece with the body 52 . FIG. 3 illustrates the present embodiment as having two prongs. However, in some embodiments, there may only be one prong 56 present, while some embodiments may utilize two or more prongs 56 . Additionally, one or more embodiments may comprise a grounding assembly 44 with one or a plurality of prongs 56 receptacles on the body 52 , such that the operator can define how many prongs 56 are to be used by attaching or detaching prongs from the prong receptacles. For example, if an operator requires only one prong, the operator may detach all prongs 56 except for one so that the other prongs are not in the way. Conversely, if an operator is welding a large or oddly shaped workpiece 14 , the operator may attach a plurality of prongs 56 to ensure a solid ground. In embodiments where a plurality of prongs 56 is utilized, the prongs 56 may or may not be identical. However, in the presently contemplated embodiment, these of two prongs, or more generally, two grounding contacts, allows for measurement and indication of the quality of the ground, as discussed below.
[0020] The prongs 56 direct the tips 68 to the desired grounding point on the workpiece 14 , generally but not necessarily being the joint 12 . Accordingly, in some embodiments, the prongs 56 may be absent, wherein the conductive tips 68 are coupled directly to the body 52 , bypassing the prongs 56 . Alternatively, some embodiments may utilize “tip holders” of shapes and configurations other than the generally shape of the prongs 56 . The prongs 56 may or may not be made of conductive material, insulated on the outside or not. In the case the prongs 56 are not made of conductive materials, there may be some other conductive path such as a wire or conductive core that runs along the prongs conductively coupling the tips 68 to the body 52 of the grounding assembly 44 . The prongs may or may not also be pliable. In applications where two workpieces are spaced from one another in the fit-up of the joint, it will generally be desired to have the contacts of the assembly form a ground with both workpieces such that the welding arc may be maintained as the process progresses between the workpieces.
[0021] FIG. 2 shows the tips 68 being in intimate contact with the workpiece 14 at the joint 12 , coupling the workpiece 14 with ground. The tips 68 are configured so that they can be well-situated on the joint 12 or elsewhere on the workpiece 14 , establishing a stable ground connection. In order to accommodate joints 12 and workpieces 14 of different configurations, the tips 68 may be configured in different shapes, sizes, from different materials, and so forth. Additionally, the tips 68 may also be removable and interchangeable with respect to the prongs 56 to accommodate different joint 12 configurations. The tip 68 can also be easily removed from the prongs 56 and discarded if damaged or worn without needing to replace the entire grounding assembly 44 . When use, the tip 68 may be made removable and interchangeable through various means of attachment to the prongs 56 , such as but not limited to having threads, magnets, snapping mechanisms, and various other attachment methods.
[0022] The tips 68 , being in contact with the workpiece, ground the workpiece 14 via a ground cable 42 . The ground cable 42 is conductively coupled to the prongs 56 at the base or terminal 70 . This completes a grounding circuit through the workpiece 14 , the ground cable 42 , and the ground terminal of the power supply 16 of the welding system 10 . In some embodiments, the ground lead 56 of the grounding assembly can be configured to also contain a communication cable so that data can be transmitted and received between the grounding assembly and the power supply 10 . Additional forms of communication are possible such as through communication lines elsewhere on the grounding assembly 44 or via Bluetooth, and so forth. The data may be sent and received from the power supply 10 as shown in FIG. 1 or some other type of processing unit such as but not limited to a computer.
[0023] In addition to providing a secure grounding method, the grounding assembly 44 also provides a means of sensing characteristic measurements, including but not limited to some indication of the quality of the ground connection. FIG. 4 diagrammatically illustrates the sensing and indication circuit 72 of one embodiment, which comprises an indication module 74 , and a transformer circuit 76 , the transformer circuit comprising an oscillator 78 , a primary winding 80 , and a set of secondary windings 82 . In the particular embodiment shown, the oscillator 78 is coupled to the transformer 76 which features a primary winding 80 and a pair of secondary windings 82 . The secondary windings 82 each comprises one end 84 which is coupled to the prongs 56 . The secondary windings 82 are connected to each other on the sides opposite the ends 84 which are coupled to the prongs. The junction of the two secondary windings 82 is also the centertap ground cable terminal 86 as more clearly shown in FIG. 4 . At the centertap ground cable terminal 86 , the ground cable 42 is coupled to the ends 84 of the transformer circuit 76 , thus grounding the workpiece via the prongs 56 and tips 68 . Additionally, the ends 84 also act as sensor leads going to the prongs 56 of the grounding assembly 44 where they are conductively coupled to the tips 68 and the workpiece 14 . In the present embodiment, the two tips, tip 1 96 and tip 2 98 now function as the sensor leads. A measurement circuit is completed through the workpiece 14 as current flows from the centertap transformer 76 to one tip 68 , through the workpiece 14 to the other tip 68 , and then back into the centertap transformer 76 . The signal then passes through a sensor 88 which feeds the measurement data to a processing circuit 90 , where measured data is stored and processed.
[0024] The processing circuit 90 can be configured in many different ways in accordance with a wide range of possible functions as known to one skilled in the art. The processing circuit 90 may carry out tasks such as calibrating and digitizing sensor values, storing data, and controlling the indication module 74 . The processing circuit 90 is coupled to a power supply 92 , which may be a battery, capacitor, or some other appropriate power source to drive the power consuming components of the circuit, Additionally, there may also be an indication module 74 coupled to the processing circuit 90 . The indication module 74 may be configured to output readouts, sounds, lights, any combination of these and other types of output indication signals. These indications may give a direct numerical representation of the measurements, in which case the operator will know how to interpret the numerical representation with respect to quality of ground. In other embodiments, the indication 74 in conjunction with the processing circuit 90 may be preprogrammed so that it references the measured value with threshold values, effectively making a decision about the quality of the ground and outputting a qualitative indication of the quality of the ground connection or other parameters. For example, there may be a green LED, a yellow LED, and a red LED such that the green LED lights up when a solid ground connection has been made, the yellow LED lights up when an unstable ground connection is detected, and the red LED lights up when the ground connection is absent. In some embodiments, there may only be two degrees of ground quality: present or absent. The processing and indication function may not always need to be used and is not necessary for the grounding function of the grounding assembly 44 . Additionally, as mentioned above, the type and degree of indication may be configured to meet a wide range of desired functions and formats. Some embodiments may include a push to test button 94 coupled to the measurement circuit to turn the function on and off.
[0025] The processing circuit 90 may also be coupled to an input controls interface 96 in some embodiments. The interface 96 allows the operator to select different functions and indication types. For example, the operator may want to see data from a previous measurement or turn an alarm on or off. Accordingly, the interface may include controls such as but not limited to buttons, touchscreens, knobs, keypads, and any combination of these and other types of existing or new input controls. The physical location of the output signals and input controls can be in various locations on the grounding assembly 44 .
[0026] While only certain features of the invention have been illustrated and described herein, many modifications and changes will occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.
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A grounding system is provided for welding applications. The system comprises a pair of contacts that are brought into close grounding contact with a workpiece, and a measurement circuit coupled to the contacts. The contacts may be urged into intimate contact with the workpiece by a biasing structure that pulls the contacts tightly against the workpiece. The measurement circuit may include a center-tap transformer having a secondary coupled to a ground lead and to the contacts. A primary winding of the transformer is coupled to an oscillator that executes a measurement test. The system may provide an indication of the quality of the ground in the form of an operator perceptible notification, a digitized value, or any other suitable form.
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[0001] This application takes priority from U.S. Provisional Patent Application Ser. No. 61/037,334, filed 18 Mar. 2008, the specification of which is hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention generally relates to implantable cardiac devices, including pacemakers, defibrillators and cardioverters, which stimulate cardiac tissue electrically to control the patient's heart rhythm. More particularly, the present invention relates to a method and apparatus for classifying of supraventricular tachyarrhythmia (SVT) from ventricular tachyarrhythmia (VT) based on morphological analysis of the intracardiac electrogram (IEGM) recorded by the implantable cardiac devices.
[0004] 2. Description of the Related Art
[0005] Implantable cardioverter-defibrillator (ICD) is a demonstrated therapy for treating life-threatening VT, including ventricular tachycardia and ventricular fibrillation. Successful ICD therapy relies on fast and accurate detection of VT. However, despite high sensitivity, one of the major limitations of the current ICD devices is the relatively low specificity for VT detection. False VT detection frequently occurs in the case of SVT, particular in the case of 1:1 AV association. Consequently, this low specificity often results in inappropriate ICD shocks delivered for SVT, causing patient's discomfort, negatively affecting their quality of life, and reducing device longevity because of unnecessary current drain.
[0006] Conventionally, the VT detection algorithm in the ICDs is based on cardiac inter-beat or RR interval analysis. Different VT zones are programmed based on predefined thresholds of RR intervals or ventricular rates. Because SVT frequently results in short RR intervals or high ventricular rates that also fall in the VT zone, enhancement of the VT detection algorithm was made by including additional criteria such as sudden onset and stability.
[0007] For dual-chamber ICDs, the discrimination of SVT from VT can be substantially enhanced by the addition of atrial sensing capability. Many types of SVT rhythms, such as atrial flutter and atrial fibrillation, can be easily distinguished from the VT by the evidence of AV dissociation. However, the challenge to discriminate SVT from VT in the presence of 1:1 AV relationship, such as during sinus tachycardia or AV nodal reentrant tachycardia, still remains.
[0008] Morphological analysis has also been used to facilitate the SVT-VT classification. Usually, a template IEGM of conducted baseline rhythm is recorded and maintained. During fast ventricular activation, the rhythm is classified as SVT if the IEGM morphology is similar to the template waveform, whereas it is classified as VT if the IEGM morphology is distinctly different from the template waveform. All morphology-based SVT-VT classification algorithms require proper alignment of the template waveform and the test IEGM.
[0009] One morphology analysis method is based on correlation analysis. However, the calculation of conventional correlation coefficient (CC) between two vectors requires extensive floating-point operation, which renders it not feasible for implementation in the low-power devices or systems. As a compromise, an algorithm may only select a small number of samples from the signal (for example 8) to calculate an alternative index termed feature correlation coefficient (FCC). Despite this simplification, the computation load is still high due to the floating-point operation. Also, the waveform morphology is unlikely to be fully characterized by the limited 8 samples, thus FCC may not accurately quantify the similarity between two waveforms. Furthermore, similar to CC, the FCC is less sensitive to the amplitude discrepancy between the signals. For example, the FCC between two signals X and Y=ρ·X, where ρ is a constant scaling factor, is always 1, despite the fact that the amplitude of Y can be significantly different than that of X. Finally, the FCC between two signals is affected by each sample amplitude of each signal, thus is sensitive to additive noise such as impulse noise and continuous random noise.
[0010] Another morphology analysis method is based on metrics that are derived from the signals. The metric used in this algorithm is the peak area of the IEGM waveform, while other metrics (weight, height, zero-crossing, etc.) may also be used. The algorithm measures the difference between the corresponding (normalized) peak areas of the test and template IEGM waveforms. Then a morphology score is generated based on the peak area difference to indicate the similarity between test and template IEGM signals. However, the metric (peak area) derived from the signal is affected by many factors, such that waveforms of different morphologies can have the same metric value. In principle, the waveform morphology is unlikely to be fully characterized by a single or multiple metrics, thus the derived morphology score may not accurately quantify the similarity between two waveforms. Moreover, such an algorithm is known to be very sensitive to the waveform alignment errors.
[0011] Wavelets, especially modified Haar wavelets, have also been used to facilitate discrimination between SVT and VT. In particular, the modified Haar wavelets were used to decompose the IEGM signal into wavelet coefficients. To compare the morphology between a test IEGM and the template waveform, their respective wavelet coefficients are compared. If the match percentage between their wavelet coefficients is greater than a threshold (e.g., 70%), then the test IEGM is considered similar to the template waveform, indicating a conducted beat. Otherwise, the test IEGM is thought to have different morphology than the template waveform, suggesting ventricular origin of the beat. However, because in practice, only limited number of wavelet coefficients are retained to represent the IEGM waveform, some subtle morphological information may be lost through the wavelet transform. As a result, the match percentage between wavelet coefficients may not accurately reflect the morphological similarity between two signals.
[0012] In view of above, there is a need to provide a novel method to accurately, efficiently, and robustly measure the morphological similarity between an IEGM signal and a template waveform, to facilitate discrimination between SVT and VT.
BRIEF SUMMARY OF THE INVENTION
[0013] It is an object of the invention to provide a device, for example an implantable cardiac device, such as a pacemaker, a defibrillator or a cardioverter, for classifying of supraventricular tachyarrhythmia (SVT) from ventricular tachyarrhythmia (VT). The device comprises means for providing a template signal and a test signal originated from an electrogram. The template signal and the test signal comprising samples. The device comprises further means for transforming at least the test signal resulting in a representation of the test signal where the sample values of the signal take integers. The device comprises further means for determining a correlation between the template signal and the test signal, and means for classifying of SVT from ventricular VT based on the correlation.
[0014] The electrogram may be an intracardiac electrogram (IEGM), a surface electrocardiogram (ECG) or a subcutaneous electrogram.
[0015] The invention provides a device which further comprises means for averaging a plurality of cycles of signals to obtain the template signal. Especially cycles of conducted ventricular IEGM signals may be used.
[0016] The invention provides a device which further comprises means for updating the template periodically or continuously after an initial template setup.
[0017] The invention provides a device which further comprises means for aligning the signals based on at least one predefined fiducial point.
[0018] A further object of the invention is providing a device which further comprises means for associating the template signal with at least two subspaces of the template signal space and means for transforming at least one of the template signal and the test signal with respect to the subspaces.
[0019] In an embodiment the means for associating the template signal with at least two subspaces comprises means for defining a first subspace comprising values which differ from the template signal values at the most by a predefined first value, and means for defining a second subspace comprising values which differ from the template signal values at the least by the predefined first value.
[0020] In an other embodiment the means for associating the template signal with at least two subspaces comprises means for associating the template signal with three subspaces, and means for defining a first subspace comprising values which differ from the template signal values at the most by a predefined first value, means for defining a second subspace comprising values which differ from the template signal values at the least by the predefined first value and at the most by a predefined second value, and means for defining a third subspace comprising values which differ from the template signal values at the least by the predefined second value.
[0021] According to another aspect of the invention the device further comprising means for generating threshold vectors bounding the subspaces, where the threshold vectors are generated by increasing or decreasing the sample values of the template signal by a predefined value.
[0022] According to yet another aspect of the invention the means for transforming comprises means for setting a sample value of the transformed signal to a first, second or third integer if the corresponding sample value of the signal belongs to the first, second or third subspace. In a special embodiment the first integer is set to 1, the second integer is set to 0 and the third integer is set to −1.
[0023] In a further embodiment of the invention the device comprises means for determining a correlation using at least the transformed test signal.
[0024] In yet a further embodiment of the invention the device comprises means for determining a correlation using only the transformed test signal.
[0025] In another embodiment the means for determining a correlation comprises means for determining an Adapted Signed Correlation Index (ASCI) as the sum of the sample values of the transformed test signal or by dividing the sum of the sample values of the transformed test signal by the number of samples.
[0026] According to an aspect of the invention the means for classifying comprises means for classifying a ventricular IEGM as being of ventricular origin if the correlation is below a predefined threshold, or as being of supraventricular origin otherwise.
[0027] According to another aspect of the invention the means for classifying comprises means for performing SVT-VT classification by a combination of determining the correlation between the template signal and the test signal and RR interval analysis.
[0028] In an embodiment the means for classifying further comprises means for incrementing a VT sample counter by 1 for a ventricular cycle that falls in the VT/VF zone if and only if the correlation value between the ventricular cycle and the template signal is below a predefined threshold.
[0029] According to yet an other aspect of the invention the means for classifying comprises means for performing SVT-VT classification by a combination of determining the correlation between the template signal and the test signal and SVT-VT classification algorithm that involves both atrial and ventricular rate and rhythm analysis.
[0030] According to yet another aspect of the invention the template signal is an atrial IEGM waveform and the means for classifying comprises means for determining the correlation between an atrial test IEGM signal with the atrial IEGM waveform in case a SVT or VT with 1:1 relationship is detected for distinguishing an intrinsic atrial event from a retrograde conducted atrial event.
[0031] It is further an object of the invention to provide a method for classifying of supraventricular tachyarrhythmia (SVT) from ventricular tachyarrhythmia (VT) using signals provided by an electrogram comprising the steps of:
providing a template signal and a test signal, the template signal and the test signal comprising samples; transforming at least the test signal resulting in a representation of the test signal where the sample values of the signal take integers; determining a correlation between the template signal and the test signal; and classifying of SVT from ventricular VT based on the correlation.
[0036] According to an aspect of the invention the signals are provided by an intracardiac electrogram (IEGM), a surface electrocardiogram (ECG) or a subcutaneous electrogram.
[0037] In an embodiment of the invention the template signal is obtained by averaging a plurality of cycles of signals, where cycles of conducted ventricular IEGM signals may be used.
[0038] In an embodiment of the invention after an initial template setup the template is updated periodically or continuously.
[0039] In another embodiment of the invention the signals are aligned based on at least one predefined fiducial point.
[0040] According to another aspect of the invention the method for classifying of SVT from VT comprises the further steps of:
associating the template signal with at least two subspaces of the template signal space and transforming at least one of the template signal and the test signal with respect to the subspaces.
[0043] In an embodiment of the invention the at least two subspaces are defined by
a first subspace comprising values which differ from the template signal values at the most by a predefined first value, and a second subspace comprising values which differ from the template signal values at the least by the predefined first value.
[0046] In another embodiment of the invention the template signal is associated with three subspaces and the three subspaces are defined by
a first subspace comprising values which differ from the template signal values at the most by a predefined first value, a second subspace comprising values which differ from the template signal values at the least by the predefined first value and at the most by a predefined second value, and a third subspace comprising values which differ from the template signal values at the least by the predefined second value.
[0050] According to an aspect of the invention the subspaces are bounded by threshold vectors.
[0051] In an embodiment of the invention the threshold vectors are obtained by increasing or decreasing the sample values of the template signal by a predefined value.
[0052] In an embodiment of the invention transforming the signals comprises assigning a first, second or third integer to a sample of the transformed signal if the corresponding sample of the signal belongs to the first, second or third subspace. The first integer may be set to 1, the second integer may be set to 0 and the third integer may be set to −1.
[0053] According to an aspect of the invention determination of the correlation is performed using the transformed test signals.
[0054] According to another aspect of the invention determination of the correlation is performed using only the transformed test signal.
[0055] In an embodiment of the invention for determining a correlation a ASCI (Adapted Signed Correlation Index) is determined as the sum of the sample values of the transformed test signal or by dividing the sum of the sample values of the transformed test signal by the number of samples.
[0056] According to an aspect of the invention a ventricular IEGM is classified as being of ventricular origin if the correlation is below a predefined threshold, or as being of supraventricular origin otherwise.
[0057] According to another aspect of the invention SVT-VT classification is performed by a combination of determining the correlation between the template signal and the test signal and RR interval analysis.
[0058] In an embodiment for a ventricular cycle that falls in the VT/VF zone a VT sample counter is increment by 1 if and only if the correlation value between the test and the template signal is below a predefined threshold.
[0059] According to yet an other aspect of the invention SVT-VT classification is performed by a combination of determining the correlation between the template signal and the test signal and SVT-VT classification algorithm that involves both atrial and ventricular rate and rhythm analysis.
[0060] According to a further aspect of the invention the template signal is an atrial IEGM waveform and determining the correlation between an atrial test IEGM signal with the atrial IEGM waveform in case a SVT or VT with 1:1 relationship is detected for distinguishing an intrinsic atrial event from a retrograde conducted atrial event.
[0061] It is further an object of the invention to provide a computer-readable storage medium storing program code for causing a data processing device to perform a method for classifying of supraventricular tachyarrhythmia (SVT) from ventricular tachyarrhythmia (VT) using signals provided by an electrogram, the method comprising the steps of:
providing a template signal and a test signal, the template signal and the test signal comprising samples; transforming at least the test signal resulting in a representation of the test signal where the sample values of the signal take integers; determining a correlation between the template signal and the test signal; and classifying of SVT from ventricular VT based on the correlation.
[0066] According to this invention, the ASCI is used to quantify the morphological similarity between an IEGM signal and a template waveform. All valid sample pairs are included in the calculation of ASCI, thus complete waveform morphology information of the two signals is retained (i.e., no loss of morphological information due to feature extraction). The calculation of ASCI is computationally efficient because no floating-point operation is necessary. Furthermore, calculation of ASCI is robust against measurement noise and minor alignment error of the signals.
[0067] According to this invention, the template waveform is created by averaging multiple cycles of conducted ventricular IEGM, which is aligned with predefined fiducial point. Preferably, the template waveform is created at high atrial rate (sinus rhythm or atrial pacing) but below the VT detection rate. The template waveform is also preferably updated periodically or dynamically to reflect the gradual change of the conducted IEGM morphology.
[0068] In a preferred embodiment, upon detection of high ventricular rate, the ASCI-based morphological analysis is activated to enhance the existing SVT-VT classification algorithm. For a short ventricular cycle, the ASCI between this cycle's IEGM and the template waveform is calculated. If the ASCI is greater than a predefined threshold, it indicates the test IEGM has similar morphology as the template waveform, suggesting this is a conducted beat. Otherwise, it indicates the test IEGM has different morphology than the template waveform, suggesting the ventricular origin of the beat.
[0069] In this invention, although the IEGM signals are used to illustrate the concept of ASCI-based morphology analysis for SVT and VT classification, it should be understood that the same method could be applied to SVT and VT classification based on surface ECG or subcutaneous electrogram signals.
[0070] The details of the invention can be understood from the following drawings and the corresponding text descriptions.
BRIEF DESCRIPTION OF THE DRAWINGS
[0071] FIG. 1 is a high-level flowchart diagram that illustrates the steps involved in automatic setup of the conducted ventricular IEGM template in an ICD.
[0072] FIG. 2 shows an example of template setup for conducted ventricular IEGM signals.
[0073] FIG. 3 shows a high-level flowchart that illustrates the steps involved in running update of the conducted ventricular IEGM template.
[0074] FIG. 4 illustrates the concept of signal alignment using multiple fiducial points.
[0075] FIG. 5 illustrates the concept of three subspaces defined by four threshold vectors that are adaptive to the template signal.
[0076] FIG. 6 shows two examples of calculating ASCI for particular application to the assessment of IEGM morphology similarity in an ICD.
[0077] FIG. 7 shows an episode of SVT and the ASCI values between the template waveform representing conducted ventricular IEGM and each of the ventricular IEGM signal.
[0078] FIG. 8 shows an episode of VT and the ASCI values between the template waveform representing conducted ventricular IEGM and each of the ventricular IEGM signal.
DETAILED DESCRIPTION OF THE INVENTION
[0079] Construction of Template Waveform
[0080] For the purpose of SVT and VT classification, the template waveform is constructed from the electrogram signal that corresponds to antegrade conducted ventricular beat. For implantable cardiac devices, the template waveform can be constructed from the ventricular IEGM corresponding to ventricular sense (VS) event that is associated with preceding atrial sense (AS) or atrial pace (AP) event.
[0081] FIG. 1 shows a high-level flowchart diagram that illustrates the steps involved in automatic setup of the conducted ventricular IEGM template in an ICD. Preferably, the template waveform is created at an atrial rate that is higher than a predefined ‘template rate’, but below the programmed VT detection rate. In a typical example, the ‘template rate’ is defined as 20 ppm below the programmed VT detection rate. The high atrial rate can be achieved at elevated sinus rhythm, for example, during stress test, or by means of high rate atrial pacing. It is also required that 1:1 AV conduction is maintained during the template setup phase.
[0082] Then the ICD collects multiple cycles of the conducted ventricular IEGM signal, which are then aligned based on predefined fiducial point, for example, the positive or negative peak, the maximum slope, the threshold crossing point, etc., as known in the art. For each cycle, the IEGM segment in a fixed window relative to the fiducial point is selected for creating the template signal. In a typical embodiment, the fiducial point is chosen as the dominant peak (positive or negative) of the ventricular IEGM, and the IEGM window spans from 50 ms before the fiducial point to 100 ms after the fiducial point.
[0083] Still refer to FIG. 1 . According to this invention, for each pair of the aligned and windowed ventricular IEGM signals, their morphological similarity is quantified by an Adaptive Signed Correlation Index (ASCI), which will be described in details in the following sections. If for any given cycle pair, the calculated ASCI is lower than a predefined threshold value, then the collected ventricular IEGM signals are considered not stable. A warning is generated by the ICD indicating the template signal is not available at the moment, and the template setup may be retried at a later time. On the other hand, if for all cycle pairs, the calculated ASCI is greater than the predefined threshold value (e.g., 0.8), then all collected ventricular IEGM cycles are considered similar, and the conducted ventricular IEGM template is created by averaging all these aligned IEGM cycles.
[0084] As discussed in more details later, the ASCI is calculated based on the definition of three subspaces which are dependent on the template signal. Thus upon creation of the conducted ventricular IEGM template, the ICD further determines the three subspaces as discussed thereinafter. Note that during the initial template setup phase when template waveform has not been available yet, to calculate the ASCI between a pair of IEGM cycles, any one of the two IEGM signals can be initialized as the tentative template signal. Based on this tentative template signal, the three subspaces can be defined, and the similarity between these two signals can be quantified by ASCI. As discussed above, only when all pairs of the collected IEGM cycles result in higher than predefined threshold ASCI values, then these cycles are considered to have similar morphology, and the true template waveform can be created.
[0085] FIG. 2 shows a particular example of template setup for conducted ventricular IEGM signals. In this example, the surface ECG, the atrial IEGM, and the ventricular IEGM are shown (left) for four cardiac cycles in sinus rhythm. Each intrinsic atrial depolarization is followed by a conducted ventricular depolarization. The ventricular IEGM morphology is consistent among the four cycles. The positive peak of the ventricular IEGM is chosen as the fiducial point, and the window size is set from 50 ms before the positive peak to 100 ms after the positive peak. Then the four cycles of ventricular IEGM are averaged to create the conducted ventricular IEGM template waveform (right).
[0086] Update of Template Waveform
[0087] According to this invention, after the initial template setup, the conducted ventricular IEGM template is preferably updated periodically or continuously to reflect the dynamic change of the conducted IEGM morphology. This template running update feature is important because the conducted ventricular IEGM waveform may gradually change over time due to different factors such as heart rate variation, circadian pattern, changes of medication, changes of electrode-tissue interface, etc.
[0088] FIG. 3 shows a high-level flowchart that illustrates the steps involved in running update of the conducted ventricular IEGM template. Preferably, the template running update is activated if and only if the atrial rate (sensed or paced) is higher than the predefined ‘template rate’ but below the programmed VT detection rate. Upon activation of the template running update, the ICD acquires one cycle of conducted ventricular IEGM (i.e., preceded by an AS or AP event) as the test signal, which is aligned with the template signal based on predefined fiducial point as discussed above. Then the ICD calculates the ASCI between the template signal and the acquired test signal. If the ASCI is lower than a predefined threshold (e.g., 0.8), then the test signal is considered different than the template signal, and no template update is performed for this test cycle. On the other hand, if the calculated ASCI is greater than the predefined threshold (e.g., 0.8), then the test signal is considered similar to the template signal, and the template signal is updated by taking the weighted average of the original template signal and the newly acquired test signal. In an exemplary embodiment, the new template is the sum of the old template signal scaled by 255/256, and the newly acquired test signal scaled by 1/256. By this means, it ensures the stability of the template waveform by retaining 255/256 of the old template signal, whereas it incorporates 1/256 of the test signal to factor in any gradual change of the conducted ventricular IEGM morphology. As discussed in more details later, the ASCI is calculated based on the definition of three subspaces which are dependent on the template signal. Thus the ICD can further adjust the three subspaces based on newly updated template signal, if the adaptive subspace feature is enabled.
[0089] Signal Alignment
[0090] One prerequisite for any morphology-based SVT-VT classification algorithms is that the test signal must be properly aligned with the template signal. Morphological analysis based on misaligned signals may yield misleading results. As discussed above, the common practice for signal alignment is based on a predefined fiducial point, such as the positive peak, the negative peak, etc. However, in some cases, the signal alignment based on a single fiducial point is not reliable.
[0091] FIG. 4 shows some examples. Panels (a) and (b) show two signal complexes that have similar morphology. Both signal complexes can be characterized by two positive peaks (P 1 , P 2 ) that have similar amplitude and one negative peak (N 1 ). If the dominant positive peak is chosen as the fiducial point, then the fiducial point will be P 1 for the signal complex shown in panel (a) but P 2 for the signal complex shown in panel (b). Similarly, panels (c) and (d) show another pair of signal complexes that have similar morphology. Both signal complexes can be characterized by two negative peaks (N 1 , N 2 ) that have similar amplitude and one positive peak (P 1 ). If the dominant negative peak is chosen as the fiducial point, then the fiducial point will be N 2 for the signal complex shown in panel (c) but N 1 for the signal complex shown in panel (d).
[0092] According to this invention, multiple fiducial points are defined for signal alignment in adjunction with ASCI-based morphological analysis. Specifically, for a given template signal representing conducted ventricular IEGM, multiple fiducial points (if available) are defined in a sequential order, that is, 1 st fiducial point, 2 nd fiducial point, 3 rd fiducial point, etc. Similar fiducal points (if available) are also identified for a test ventricular IEGM signal. For example, for the signals shown in panels (a) and (b) of FIG. 4 , the fiducial points can be defined in the following order: dominant positive peak (1 st fiducial point; P 1 in (a) and P 2 in (b)), dominant negative peak (2 nd fiducial point; N 1 in both (a) and (b)), secondary positive peak (3 rd fiducial point; P 2 in (a) and P 1 in (b)). Similarly, for the signals shown in panels (c) and (d) of FIG. 4 , the fiducial points can be defined in the following order: dominant positive peak (1 st fiducial point; P 1 in both (c) and (d)), dominant negative peak (2 nd fiducial point; N 2 in (c) and N 1 in (d)), secondary negative peak (3 rd fiducial point; N 1 in (c) and N 2 in (d)).
[0093] To compare the morphology of the test signal and the template signal, the two signals are first aligned with the 1 st fiducial point, and their ASCI value is calculated. If the resulting ASCI value is higher than a predefined threshold (e.g., 0.8), then it indicates the two signals have similar morphology (as described in details below). The signal alignment is considered valid, and no further calculation is needed. On the other hand, if the resulting ASCI value is lower than the predefined threshold (e.g., 0.8), then it indicates the two signals have different morphology (as described in details below). Then the signals are re-aligned with the 2 nd fiducial point (if available for both signals), and their ASCI value is re-calculated. If the re-calculated ASCI value is higher than the predefined threshold (e.g., 0.8), then it indicates misalignment for the 1 st fiducial point, but the alignment based on the 2 nd fiducial point is valid. The signals are considered to have similar morphology and no further calculation is needed. Similar test can be performed for the 3 rd fiducial point (if available for both signals) if the ASCI value obtained for the 2 nd fiducial point is still lower than the predefined threshold (e.g., 0.8). No further test is needed if a fiducial point is only available for one signal but not the other signal. If all ASCI values are below the predefined threshold (e.g., 0.8), no matter which fiducial point is chosen, then it is determined that the test signal and the template signal have different morphology.
[0094] According to the experience of the present inventors, using two fiducial points (e.g., dominant positive peak and dominant negative peak) for signal alignment can effectively solve most of the signal misalignment problems caused by using a single fiducial point.
[0095] Definition of Adaptive Subspaces
[0096] Refer to FIG. 5 . Let R denote the ventricular IEGM signal space that spans from V min to V max , where V min is the minimum amplitude and V max is the maximum amplitude that could be measured by the ventricular sensing channel. Divide R into three subspaces R P , R Z , and R N such that R=R P ∪R Z ∪R N and R P ∩R Z =R P ∩R N =R Z ∩R N =Ø, where ∪ is the union operator, ∩ is the intersection operator, and Ø represents the null space. That is, the three subspaces are non-overlapping yet all together they span the whole signal space. For convenient purpose, in the following descriptions, we term R P as the positive subspace, R Z as the zero subspace, and R N as the negative subspace.
[0097] Still refer to FIG. 5 . According to this invention, all three subspaces (R P , R Z , R N ) are adaptive to the template signal representing conducted ventricular IEGM morphology. In a preferred embodiment, four threshold vectors TL D , TL P , TU P , TU D are defined from the template signal X. Denote X=[x( 1 ), x( 2 ), . . . , x(L)], where L is the number of samples in signal X. Further denote TL P =[tlp( 1 ), tlp( 2 ), . . . , tlp(L)] as the proximal lower threshold vector, TL D =[tld( 1 ), tld( 2 ), . . . , tld(L)] as the distal lower threshold vector, TU P =[tup( 1 ), tup( 2 ), . . . , tup(L)] as the proximal upper threshold vector, and TU D =[tud( 1 ), tud( 2 ), . . . , tud(L)] as the distal upper threshold vector. These threshold vectors are defined such that TL D ≦TL P ≦X≦TU P ≦TU D , or specifically, tld(i)≦tlp(i)≦x(i)≦tup(i)≦tud(i), for 1≦i≦L. The positive subspace R P is defined as the region bounded by TL P and TU P , the negative subspace R N is defined as the region above TU D or below TL D , and the zero subspace R Z is defined as the region bounded between TU P and TU D , and that between TL D and TL P . Obviously, a sample in R P is proximal to the template, a sample in R N is distal to the template, and a sample in R Z is at intermediate distance to the template.
[0098] According to an exemplary embodiment of the present invention, the four threshold vectors are defined from the template signal according to the following equations:
[0000] TU P =X+ α·max(abs( X ))
[0000] TL P =X− α·max(abs( X ))
[0000] TU D =X+ β·max(abs( X ))
[0000] TL D =X− β·max(abs( X ))
[0099] Here, max(abs(X)) is the peak absolute amplitude of the template signal, α and β are programmable scaling coefficients that satisfy 0<α<β. In a typical example, α=0.25 and β=0.5, and the resulting threshold vectors are symmetric around the template signal.
[0100] Obviously, there are numerous other means to define the four threshold vectors so that they are adaptive to the template signal X, for example, either based on sample-by-sample amplitude of X, or based on specific features of X, such as its maximum, minimum, max absolute, mean, median, etc., or their combinations. Also, the upper threshold vectors and the lower threshold vectors can be symmetric or asymmetric around the template signal.
[0101] As illustrated in FIG. 1 , after automatic setup of the conducted ventricular IEGM template, the three subspaces can be defined from four threshold vectors that are adaptive to the template signal by means of the method described above. Similarly, during the template running update as illustrated in FIG. 3 , after the template signal is updated by taking the weighted average of the old template signal and the new test signal, the three subspaces can be adjusted by redefining the threshold vectors based on the new template.
[0102] Signal Trichotomization
[0103] To calculate the ASCI between two IEGM signals, both signals are first trichotomized based on three subspaces that are adaptive to the defined template signal.
[0104] Denote S as the three-value set {−1, 0, 1}. Assume X=[x( 1 ), x( 2 ), . . . , x(L)] is a ventricular IEGM signal, that is, x(i) ε R for i=1, 2, . . . L, where L is the number of samples in signal X. Trichotomization of signal X is an operation that maps the signal from R space to S space. Specifically, denote TX=[tx( 1 ), tx( 2 ), . . . , tx(L)] as the trichotomized signal of X, where tx(i) ε S for i=1, 2, . . . L. Then the trichotomization is formulated as, for
[0000]
tx
(
i
)
=
{
1
if
x
(
i
)
∈
R
P
0
if
x
(
i
)
∈
R
Z
-
1
if
x
(
i
)
∈
R
N
[0105] In other words, signal X is trichotomized to TX by converting all its data samples to values selected from {−1, 0, 1}, based on which subspace each data sample belongs to.
[0106] In a typical embodiment, signal X is the template signal representing conducted ventricular IEGM morphology, and ASCI(X,Y) measures the similarity between a test ventricular IEGM signal Y and the template signal X. For the template signal X, all elements of its trichotomized signal TX are 1 because all samples of X are within the positive subspace R P . For another signal Y, its trichotomized signal TY will have more 1s if more samples of Y are close to the corresponding samples of X, i.e., Y is similar to X. As Y gradually deviates from X, its trichotomized signal TY has less 1s, more 0s, and eventually more −1s.
[0107] Calculation of ASCI
[0108] Assume X=[x( 1 ), x( 2 ), . . . , x(L)] and Y=[y( 1 ), y( 2 ), . . . , y(L)] are two signals in R, and each has L samples. Given defined subspaces R P , R Z , and R N (which are adaptive to the template signal), X is trichotomized to TX=[tx( 1 ), tx( 2 ), . . . , tx(L)], and Y is trichotomized to TY=[ty( 1 ), ty( 2 ), . . . , ty(L)]. The ASCI between X and Y, or ASCI(X,Y), which measures the similarity between X and Y, is defined by the following formula:
[0000]
A
S
C
I
(
X
,
Y
)
=
TX
∘
TY
TX
∘
TX
·
TY
∘
TY
[0109] Here, the symbol ∘ denotes the signed correlation product (SCP) of two trichotomized vectors, and is defined by the following formula:
[0000]
TX
∘
TY
=
∑
i
=
1
L
tx
(
i
)
⊗
ty
(
i
)
[0110] Here, the symbol denotes the signed correlation product (SCP) between two trichotomized scalars, and is defined by the following formula:
[0000]
tx
(
i
)
⊗
ty
(
i
)
=
{
1
if
tx
(
i
)
=
ty
(
i
)
-
1
if
tx
(
i
)
·
ty
(
i
)
=
-
1
0
otherwise
[0111] Accordingly, if tx(i)=ty(i), their SCP is 1. In this case, the sample pair x(i) and y(i) are considered concordant, meaning that they are in the same subspace. Specifically, both are in the positive subspace if tx(i)=ty(i)=1; or both are in the negative subspace if tx(i)=ty(i)=−1; or both are in the zero subspace if tx(i)=ty(i)=0.
[0112] On the other hand, if tx(i)·ty(i)=−1, their SCP is −1. In this case, the sample pair x(i) and y(i) are considered discordant. Specifically, it occurs when tx(i)=1 and ty(i)=−1, or tx(i)=−1 and ty(i)=1. In both cases, one sample is in the positive subspace whereas the other sample is in the negative subspace.
[0113] Otherwise, the case must be either tx(i)=0 and ty(i)≠0, or tx(i)≠0 and ty(i)=0, and their SCP is 0. In this case, the sample pair x(i) and y(i) are considered neither concordant, nor discordant. Specifically, one sample is within the zero subspace, and the other sample is either in the positive subspace or in the negative subspace.
[0114] According to the above definition, the SCP of two trichotomized vectors (TX∘TY) is the sum of the SCP of all sample pairs tx(i) ty(i), for i=1 . . . L. Therefore, the SCP of two trichotomized signals will be increased by each pair of concordant samples (+1), decreased by each pair of discordant samples (−1), and not affected otherwise (neither concordant nor discordant sample pair).
[0115] For two identical signals, all corresponding sample pairs are concordant. Therefore, for above defined TX and TY, it is evident that TX∘TX=L and TY∘TY=L. Consequently, the formula for calculating ASCI(X,Y) defined above can be simplified to:
[0000]
A
S
C
I
(
X
,
Y
)
=
TX
∘
TY
L
[0116] As discussed above, in a typical embodiment, signal X is the template signal representing conducted ventricular IEGM morphology, and all elements of its trichotomized signal TX are 1 because all samples of X are within the positive subspace. Therefore, the formula for calculating ASCI(X,Y) defined above can be further simplified to:
[0000]
A
S
C
I
(
X
,
Y
)
=
∑
i
=
1
L
ty
(
i
)
L
[0117] In other words, the ASCI(X,Y) can be simply calculated as the accumulative sum of all trichotomized samples of test signal Y normalized by the number of samples.
[0118] Properties of ASCI
[0119] Now refer to FIG. 6 , which shows two examples of calculating ASCI for particular application to the assessment of IEGM morphology similarity in an ICD. In these examples, signal X (blue trace) is the template signal representing conducted ventricular IEGM. The four threshold vectors are defined based on the template signal according to the method illustrated in FIG. 5 . Then the test IEGM signal Y (red trace) is trichotomized, and the corresponding ASCI(X,Y) is calculated as described above. In panel (a), the calculated ASCI(X,Y) is 0.90, whereas in panel (b), the resulting ASCI(X,Y) is 0.08. Assuming a predefined ASCI threshold of 0.50, then the supra-threshold ASCI(X,Y) obtained in panel (a) indicates X and Y have similar morphology. Contrarily, the sub-threshold ASCI(X,Y) obtained in panel (b) indicates X and Y have different morphology.
[0120] Therefore, ASCI(X,Y) provides a quantitative measure of the similarity between signals X and Y. The definition of ASCI is compatible to the conventional definition of Pearson's correlation coefficient (CC). Similar to CC, ASCI(X,Y) is a normalized index ranging from −1 to +1. If signals X and Y have similar morphology, they will have more concordant sample pairs, and ASCI(X,Y) will approach +1. On the other hand, if signals X and Y have different morphology, they will have fewer concordant sample pairs, and ASCI(X,Y) will be less. If most sample pairs of X and Y are discordant, then ASCI(X,Y) will approach −1. However, the ASCI is advantageous compared to Pearson's CC, due to at least three reasons:
[0121] First, the calculation of Pearson's CC requires extensive floating-point operation including multiplication, division, and square root. On the other hand, the calculation of ASCI only requires comparison and summation. The threshold vectors that are used to define subspaces can be automatically determined from the template signal, through simple operations such as scaling (bit shifting), adding/subtracting, thresholding, etc. The normalization operation (divided by L) can be omitted because the total number of samples (L) is a known constant. For the purpose of SVT-VT classification, the ASCI will be mainly used for comparison with predefined or user-programmable threshold to determine if two signals have similar morphology. In this case, the threshold can be defined in the form of X-out-of-Y criterion, or by means of bit shifting operation (e.g., to obtain L/2, 3L/4, 7L/8, etc.). Therefore, the calculation of ASCI is computationally much more efficient, and can be easily implemented in firmware or hardware of the ICD.
[0122] Second, Pearson's CC is a parametric measure of linear relationship, and it does not account for the amplitude difference between signals. On the other hand, the calculation of ASCI takes amplitude information into consideration. For the examples shown in FIG. 5 where the subspaces are defined by four threshold vectors which are further adaptive to the template signal X, a high ASCI(X,Y) value requires X and Y must stay close and have similar amplitude throughout the signal length (that is, Y must be bounded by proximal upper and lower threshold vectors around signal X); otherwise, low ASCI(X,Y) value is obtained.
[0123] Thirdly, Pearson's CC is affected by each sample amplitude of each signal, thus is sensitive to additive noise such as impulse noise or continuous random noise, as well as sensitive to slight yet normal signal variation. On the other hand, the ASCI(X,Y) is calculated based on trichotomized signals TX and TY, and signal trichotomization is further based on subspaces R P , R Z , and R N that are adaptive to the template signal. Different means to define these subspaces can provide different degrees of tolerance of signal variation. Thus a noise-free signal and the same signal added with noise could have identical trichotomized vectors. Therefore, by properly designing subspaces according to specific application and/or prior knowledge of the signal, the ASCI can be more tolerant to additive noise and normal signal variation than the Pearson's CC.
[0124] SVT-VT Classification
[0125] Because the ASCI can reliably and efficiently measure the morphological similarity between signals, it can be used to facilitate SVT and VT classification in an ICD.
[0126] FIG. 7 shows an episode of SVT with 3:2 Wenckebach periodicity. In this example, the surface ECG, the atrial IEGM, and the ventricular IEGM are shown. The template waveform representing conducted ventricular IEGM was created by means of beat averaging as illustrated in FIG. 1 and FIG. 2 , and the three subspaces were created by defining four threshold vectors that are adaptive to the template waveform as illustrated in FIG. 5 . Then each ventricular IEGM cycle (test signal) was aligned with the template signal based on predefined fiducial point as discussed above, and the ASCI value between the test signal and the template signal was calculated. As shown in the figure, the resulting ASCI values for the first 8 ventricular cycles are high (range from 0.76 to 1.0), indicating the ventricular IEGM has similar morphology to the template signal, thus implying they are antegrade conducted beats. For the last cycle that represents a ventricular extrasystole (VES), however, the resulting ASCI value is low (0.15), indicating the ventricular IEGM has different morphology than the template signal, thus implying ventricular origin of the beat.
[0127] FIG. 8 shows an episode of VT with higher ventricular rate than the atrial rate. In this example, the surface ECG, the atrial IEGM, and the ventricular IEGM are shown. Similarly, the template waveform representing conducted ventricular IEGM was created by means of beat averaging as illustrated in FIG. 1 and FIG. 2 , and the three subspaces were created by defining four threshold vectors that are adaptive to the template waveform as illustrated in FIG. 5 . Then each ventricular IEGM cycle (test signal) was aligned with the template signal based on predefined fiducial point as discussed above, and the ASCI value between the test signal and the template waveform was calculated. As shown in the figure, the resulting ASCI values are consistently low (range from 0.06 to 0.26), indicating the ventricular IEGM has different morphology than the template signal, thus implying ventricular origin of the beats.
[0128] In one embodiment, the SVT-VT classification is made by means of RR interval analysis combined with ASCI-based morphological analysis of the ventricular IEGM. For example, there exist VT detection algorithms which maintains an up/down VT sample counter. For single chamber devices with ventricular-only sensing, the counter is increased by each RR interval within the predefined VT/VF zone, and is decreased by each RR interval within the predefined sinus zone. A VT episode is detected if the VT sample counter exceeds a predefined threshold (e.g., 12). As known in the art, the sudden onset and RR interval stability criteria can be applied to enhance the performance of SVT-VT classification. According to this invention, such an RR interval analysis based VT detection algorithm can be further enhanced by evaluating the ASCI value between the template waveform representing conducted ventricular IEGM and each cycle of ventricular IEGM (test signal). In a preferred embodiment, a short ventricular cycle that falls in the VT/VF zone is counted toward VT (i.e., increment VT sample counter by 1) if and only if the ASCI value between the test signal and the template waveform is below a predefined threshold (e.g., 0.5). This implies that the two signals have different morphology, thus confirming ventricular origin of the ventricular beat. Otherwise, it implies that the two signals have similar morphology, thus indicating supraventricular origin of the ventricular beat. Consequently, the VT sample counter does not change or decreases by a delta value. For example, the VT sample counter does not change if 0.5≦ASCI<0.7, or is decreased by ¼ if 0.7≦ASCI<0.8, or is decreased by ½ if 0.8≦ASCI<0.9, or is decreased by 1 if 0.9≦ASCI≦1.
[0129] In another embodiment, the ASCI-based morphological analysis is used to enhance the SVT-VT classification algorithm that involves both atrial and ventricular rate and rhythm analysis. Such algorithms analyze the average heart rate, the rate stability, and the beat-to-beat relation between atrial and ventricular activity (AV relation). Multiple detection criteria are used to determine if a short cycle (in VT zone) belongs to VT or SVT. Detailed description of detection criteria of such a SVT-VT classification algorithm is given in: Theuns et al., ‘Initial clinical experience with a new arrhythmia detection algorithm in dual chamber implantable cardioverter defibrillators’, Europace 2001; 3:181-186, and Sinha et al., ‘Clinical experience with a new detection algorithm for differentiation of supraventricular from ventricular tachycardia in a dual-chamber defibrillator’, JCE 2004; 15: 646-652.
[0130] In known SVT-VT classification algorithms, the VT sample counter is based on both RR interval and the detection decision criteria. Similarly, a VT episode is detected if the VT sample counter exceeds a predefined threshold (e.g., 12). In a typical example, the VT sample counter is increased by 1 if the RR interval is in VT zone and the cycle meets VT detection criteria. The VT sample counter is decreased by ¼ for sinus tachycardia (ST) with 1:1 AV relationship, and decreased by 1 for other SVT (e.g., atrial fibrillation, atrial flutter) interval in the VT zone. The VT sample counter is also decreased by 1 if the RR interval is in sinus interval zone. In addition, VT sample counter does not change (freeze) for a cycle in ventricular fibrillation (VF) zone. A separate counter is maintained to count the cycles in VF zone for VF detection based on conventional X-out-of-Y criterion (e.g., 8 out of 12 beats having a short RR interval in VF zone).
[0131] According to the present invention, VT detection algorithm can be further enhanced by evaluating the ASCI value between the template waveform representing conducted ventricular IEGM and each cycle of ventricular IEGM (test signal).
[0132] In an exemplary embodiment, a short ventricular cycle that meets the VT detection criteria is counted toward VT (i.e., increment VT sample counter by 1) if and only if the ASCI value between the test signal and the template waveform is below a predefined threshold (e.g., 0.5). This implies that the two signals have different morphology, thus confirming ventricular origin of the ventricular beat. Otherwise, it implies that the two signals have similar morphology, thus indicating supraventricular origin of the ventricular beat. Consequently, the VT sample counter does not change or decreases by a delta value. For example, the VT sample counter does not change if 0.5≦ASCI<0.7, or is decreased by ¼ if 0.7≦ASCI<0.8, or is decreased by ½ if 0.8≦ASCI<0.9, or is decreased by 1 if 0.9≦ASCI≦1.
[0133] Yet in another exemplary embodiment, the ASCI-based morphology analysis is only activated to facilitate SVT-VT detection when the algorithm which is based on both atrial and ventricular rate and rhythm analysis has difficulty to determine SVT or VT rhythm, for example, when the algorithm makes the decision of SVT or VT with 1:1 AV relationship. On the contrary, when the algorithm has high confidence of its decision, for example, detection of VT when ventricular rate is higher than atrial rate, or detection of atrial fibrillation if atrial rate is higher than ventricular rate and ventricular rate is unstable, then ASCI-based morphology analysis is not needed.
[0134] According to yet another embodiment of the present invention, the ASCI-based morphology analysis is applied to atrial IEGM to facilitate SVT-VT detection when the algorithm which is based on both atrial and ventricular rate and rhythm analysis makes the decision of SVT or VT with 1:1 AV relationship. Specifically, an atrial IEGM template waveform representing intrinsic atrial depolarization is created and maintained in a similar manner as the ventricular IEGM template. When the algorithm detects SVT or VT with 1:1 AV relationship, the atrial IEGM is compared with the atrial template waveform and their ASCI value is calculated. If the resulting ASCI is higher than a predefined threshold (e.g., 0.5), then it indicates that the two signals have similar morphology. This implies the intrinsic nature of the atrial IEGM, thus the beat can be counted toward SVT. On the other hand, if the resulting ASCI is lower than the predefined threshold (e.g., 0.5), then it indicates that the two signals have different morphology. This suggests that the atrial IEGM may be the result of retrograde conduction, thus the beat can be counted toward VT.
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A device for classifying of supraventricular tachyarrhythmia (SVT) from ventricular tachyarrhythmia (VT) comprising means for providing a template signal and a test signal originated from an electrogram, the template signal and the test signal comprising samples, means for transforming at least the test signal resulting in a representation of the test signal where the sample values of the signal take integers, means for determining a correlation between the template signal and the test signal and means for classifying of SVT from ventricular VT based on the correlation.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional application of U.S. application Ser. No. 10/381,855 filed Oct. 8, 2003, now U.S. Pat. No. 7,538,097; which is a 35 USC §371 National Stage application of International Application No. PCT/US01/42329 filed Sep. 25, 2001; which claims the benefit under 35 USC §119(e) to U.S. Application Ser. No. 60/235,321 filed Sep. 26, 2000, now abandoned. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.
BACKGROUND OF INVENTION
1. Field of the Invention
The present invention relates to the field of immunosuppression, more specifically to methods of inhibiting antigen presentation and transplant rejection.
2. Background Information
A number of diseases are treated by the transplantation of tissue donated by other humans (allografts) or obtained from animals (xenografts). For example, insulin-dependent diabetes is often treated by transplantation of insulin-secreting pancreatic islet cells. While the transplanted cells may have the capacity to perform the desired function (e.g., secretion of insulin in response to rising levels of glucose), such grafts typically fail as a result of immunological rejection. Shortly after transplantation, cells of the immune system of the recipient recognize the allogeneic or xenogeneic cells as foreign and proceed to attack the graft through both humoral and cellular routes. Allogeneic or xenogeneic cells are initially recognized by the recipient's immune system through antigenic determinants expressed on the surface of the cells. The predominant antigens recognized as “non-self” are major histocompatibility complex class I and class II antigens (MHC class I and class II). MHC class I antigens are expressed on virtually all parenchymal cells (e.g., pancreatic islet cells), in contrast, MHC class II antigens are expressed on a limited number of cell types, primarily B cells, macrophages, dendritic cells, Langerhans cells and thymic epithelium. The interaction of foreign MHC antigens with the T cell receptor on host T cells causes these cells to become activated. Following activation, the T cells proliferate and induce effector functions which result in cell lysis and destruction of the transplanted cells.
For transplantation to be a viable therapeutic option, approaches are needed to inhibit rejection of transplanted cells by the immune system of the recipient. One method for inhibiting this rejection process is by administration of drugs that suppress the function of the immune system. While drugs such as cyclophosphamide and cyclosporin effectively inhibit the actions of the immune system and thus allow graft acceptance, their use can cause generalized, non-specific immunosuppression in the graft recipient which leaves the recipient susceptible to other disorders such as infection and tumor growth. Additionally, administration of immunsuppressive drugs is often accompanied by other serious side effects such as renal failure and hypertension.
It has been shown that it is possible to alter an antigen on the surface of a cell prior to transplantation to “mask” the antigen from normal recognition by cells of the recipient's immune system (see, Faustman and Coe, Science 252:1700-1702 (1991) and WO 92/04033). For example, MHC class I antigens on transplanted cells can be altered by contacting the cells with a molecule which binds to the antigen, such as an antibody or fragment thereof (e.g., a F(ab′)2 fragment) prior to transplantation. This alteration of MHC class I antigens modifies the interaction between the antigens on the cells and T lymphocytes in the recipient following transplantation to thereby inhibit rejection of the transplanted cells. Additional methods for reducing the immunogenicity of an allograft or xenograft to inhibit rejection of the graft following transplantation in a host are needed.
T-cell mediated immune responses are thought to be the primary mechanism of organ transplant rejection and a driving component of various auto-immune diseases. This T-cell mediated immune response is initially triggered by helper T-cells which are capable of recognizing specific antigens. These helper T-cells may be memory cells left over from a previous immune response or naive cells which are released by the thymus and may have any of an extremely wide variety of antigen receptors. When one of these helper T-cells recognizes an antigen present on the surface of an antigen presenting cell (APC) or a macrophage in the form of an antigen-MHC complex, the helper T-cell is stimulated by signals emanating from the antigen-specific T-cell receptor, co-receptors, and IL-1 secreted by the APC or macrophage, to produce IL-2. The helper T-cells then proliferate. Proliferation results in a large population of T-cells which are clonally selected to recognize a particular antigen. T-cell activation may also stimulate B-cell activation and nonspecific macrophage responses. Some of these proliferating cells differentiate into cytotoxic T-cells which destroy cells having the selected antigen. After the antigen is no longer present, the mature clonally selected cells will remain as memory helper and memory cytotoxic T-cells, which will circulate in the body and recognize the antigen should it show up again. If the antigen triggering this response is not a foreign antigen, but a self antigen, the result is auto immune disease; if the antigen is an antigen from a transplanted organ, the result is graft rejection. Consequently, it is desirable to be able to regulate this T cell mediated immune response.
The current paradigms of immunosuppressive agents reflects the progress in understanding the cellular and molecular mechanisms which mediate graft rejection. Six paradigms represent the evolution of immunosuppressive strategies for organ transplantation to date. The proliferation paradigm advances agents which interrupt lymphocyte cell division (azathioprine, cyclophosphamide, mycophenolic acid). The depletion paradigm conscripts drugs that bind to lymphocyte cell surface markers, thereby producing cell lysis and/or inactivation (polyclonal ATGAM and thymoglobulin, and monoclonal OKT3 antilymphocyte antibodies). The cytokine paradigm uses agents that interrupt lymphocyte maturational events; eg, synthesis (calcineurin inhibitors; cyclosporine/tacrolimus), binding to surface receptors (anti-CD25 mAbs), or signal transduction phases of cytokine stimulation (sirolimus). The introduction of calcineurin inhibitors markedly reduces the rate of acute rejection episodes and increases short-term graft survival rates; nephrotoxicity and chronic allograft attrition remain as unanswered challenges. The cyclosporine A (CsA) sparing property of sirolimus permits the use of lower exposure to calcineurin agents, allows for early withdrawal of steroid therapy, and may delay allograft senescence. Furthermore, the combination of SRL with anti-IL-2R mAbs proffers an induction approach which allows prolonged periods of holiday from calcineurin inhibitors. To address the tissue nonselectivity of the calcineurin and mTOR inhibitors, which presumably causes the drug toxicities, new agents are being developed to selectively inhibit the T cell target Janus Kinase 3. In the co-stimulation paradigm, the accessory signals generated by antigen-presenting cells are interrupted by distinct agents: the receptor conjugate CTLA4-immunoglobulin and anti-B7 or anti-CD40 ligand mAbs. Another set of drugs (selectin blocking agents, anti-ICAM-1 antisense deoxy oligonucleotides, and the lymphocyte homing inhibitor FTY720) seeks to modulate the ischemia-reperfusion injury, which exacerbates cytokine-mediated events in the donor and the subsequent procurement injury and may also accelerate the progression of transplant senescence. Finally, the transplantation tolerance paradigm is based on the development of strategies which distort alloimmune recognition by antigen reactive cells (MHC peptides or proteins), produce anergy (costimulation blockers), functional inactivation, or deletion of antigen-reactive cells (donor bone marrow infusions and gene therapy).
Thus, the common paradigms today focus upon either T-cell expansion or extravasation into the rejected tissue site. However, a relatively ignored component of immune rejection is antigen presentation, which we now document herein as an excellent target for intervention through the use of poorly catabolized polymers.
SUMMARY OF THE INVENTION
The present invention relates to the discovery that foreign antigen presentation can be inhibited in an animal by saturating the antigen presenting cells (APC's) with non immunogenic agents. In general, methods are provided to saturate antigen-presenting cells with poorly catabolized non immunogenic-polymers that are readily phagocytosed by APC's such that the presentation of immunogenic foreign antigens are effectively inhibited.
One embodiment of the present invention provides a method of inhibiting antigen presentation in an animal by administering to an animal a poorly catabolized polymer in an amount sufficient to inhibit presentation of at least one antigen to the immune system of the animal. The at least one antigen can be derived from a variety of sources such as, but not limited to, allografted cells, xenografted cells, isolated stem cells and gene therapy formulations. Furthermore, the at least one antigen can be derived from a source that is substantially free of nucleic acid.
Another embodiment of this invention provides a method of inhibiting the rejection of cells transplanted in animals by administering a poorly catabolized polymer to an animal then introducing, into the animal, cells that are capable of expressing at least one antigen. Cells that are capable of expressing at least one antigen can be but are not limited to allografted cell, xenografted cells and isolated stem cells.
Yet another embodiment of the present invention provides a method of inhibiting an immune response to a gene therapy formulation by administering a poorly catabolized polymer to an animal then introducing, into the animal, a gene therapy formulation that is capable of producing at least one antigen.
In each of the previously described methods, the time of administration of the poorly catabolized polymer can be altered. Specifically, the poorly catabolized polymer can be administered to the animal before at least one antigen is presented the immune system of the animal. The poorly catabolized polymer can also be administered to the animal before exposing the animal to at least one antigen. Even more specifically, the poorly catabolized polymer is administered to the animal more than 24 hours prior to exposing the animal to at least one antigen.
Other embodiments of this invention describe administration of the poorly catabolized polymer to an animal in the presence of other immunosuppressive agents. In still other embodiments the poorly catabolized polymer comprises a dextran solution.
The present invention also provides a pharmaceutical composition comprising a poorly catabolized polymer wherein the poorly catabolized polymer is used to inhibit the presentation of at least one antigen to the immune system of an animal. In some of these compositions, the poorly catabolized polymer comprises a dextran solution.
Still another embodiment of the present invention provides a use of a poorly catabolized polymer in the preparation of a medicament for treating rejection by the immune system of an antigenic material introduced into an animal. This antigenic material can comprise a cell. It can also comprise a gene therapy formulation. In some uses, the poorly catabolized polymer is dextran.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same becomes better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein:
FIG. 1 is a schematic which illustrates the chemical structure of a portion of a dextran polymer.
FIG. 2 is a graph which shows the effect of pre-administration of a dextran solution on the survival of human HT1080 cell xenografts that are grown inside titanium chambers which have been implanted in C57BI/6 mice.
FIG. 3 is a graph which shows the effect of the route of dextran administration on the survival of human HT1080 cell xenografts that are grown inside titanium chambers which have been implanted in C57BI/6 mice.
FIG. 4 is a graph which illustrates the effect of the time of administration of dextran on the survival of human HT1080 cell xenografts that are grown inside titanium chambers which have been implanted in C57BI/6 mice.
FIG. 5 is a graph which plots the survival of Murine NOD-derived beta stem cell isografts in immunocompatible C57BI/6 mice.
FIG. 6 is a graph which plots the survival of a Murine NOD-derived beta stem cell allograft in Balb/c mice.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Dextran is a polymer of anhydroglucose. FIG. 1 shows the unit structure of a typical a polymer of dextran. Approximately 95% of the dextran polymer is composed of D-glucose molecules having α(1→6) linkages (Rankinet et al., J. Am. Chem. Soc. 76:4435 (1954)). The remaining 5% is composed of glucose molecules linked together by α(1→3) glycosidic bonds. These α(1→3) linkages account for the branching of the dextran polymer. Conflicting data on the branch lengths implies that the average branch length is less than three glucose units. However, other methods indicate branches of greater than 50 glucose units exist.
The molecular weight of a dextran polymer affects its structure. Native dextran has been found to have a molecular weight (MW) in the range of 9 million to 500 million Daltons (Da). This molecular weight range corresponds roughly to dextrans having between 50,000 and 2.8 million glucose molecules. Many of the more commonly used dextrans are of lower MW than the native polymers. These lower MW dextrans exhibit slightly less branching and have a more narrow range of MW distribution than the native polymers. Dextrans with MW greater than 10,000 glucose molecules behave as if they are highly branched. However, as the MW increases, dextran molecules attain greater symmetry. Dextrans with MW of 2,000 to 10,000 glucose molecules exhibit the properties of an expandable coil. At MWs below 2,000 glucose molecules, dextran is more rod-like.
There are a variety of techniques that are commonly used to determine the MW of dextran polymers. For example, the MW of dextran can be measured by one or more of the following methods: low angle laser light scattering, size exclusion chromatography, copper-complexation and anthrone reagent colorometric reducing-end sugar determination and viscosity.
Most dextrans are derived from Leuconostoc mesenteroides , strain B 512. Shorter dextran polymers of various MWs are then produced by limited hydrolysis and fractionation although exact methods are held proprietary. In general, however, fractionation of these polymers can be accomplished by size exclusion chromatography or ethanol fractionation in which the largest MW dextrans precipitate first.
Pharmaceutically acceptable compositions contemplated for use in the practice of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more of the active compounds contemplated for use herein, as active ingredients thereof, in admixture with an organic or inorganic carrier or excipient suitable for nasal, enteral or parenteral applications. The active ingredients may be compounded, for example, with the usual non-toxic, pharmaceutically or physiologically acceptable carriers for tablets, pellets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, suppositories, solutions, emulsions, suspensions, hard or soft capsules, caplets or syrups or elixirs and any other form suitable for use. In addition auxiliary, stabilizing, thickening and coloring agents may be used. The active compounds contemplated for use herein are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the target process, condition or disease.
In addition, such compositions may contain one or more agents selected from flavoring agents (such as peppermint oil of wintergreen or cherry), coloring agents, preserving agents, and the like, in order to provide pharmaceutically elegant and palatable preparations. Tablets containing the active ingredients in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate, sodium phosphate, and the like; (2) granulating and disintegrating agents, such as corn starch, potato starch, alginic acid, and the like; (3) binding agents, such as gum tragacanth, corn starch, gelatin, acacia, and the like; and (4) lubricating agents, such as magnesium stearate, stearic acid, talc, and the tike. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. The tablets may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.
When formulations for oral use are in the form of hard gelatin capsules, the active ingredients may be mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin, or the like. They may also be in the form of soft gelatin capsules wherein the active ingredients are mixed with water or an oil medium, for example, peanut oil, liquid paraffin, olive oil and the like.
Formulations may also be in the form of a sterile injectable suspension. Such a suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,4-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
Formulations contemplated for use in the practice of the present invention may also be administered in the form of suppositories for rectal administration of the active ingredients. These compositions may be prepared by mixing the active ingredients with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols (which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the active ingredients), and the like.
In addition, sustained release systems, including semi-permeable polymer matrices in the form of shaped articles (e.g., films or microcapsules) can also be used for the administration of the active compound employed herein. The poorly catabolized polymer can also be provided as a unit dosage such as a septum-sealed vial, either lyophilized or in aqueous solution.
EXAMPLES
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to carry out the invention. The examples are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to the numbers disclosed herein (e.g. amounts, temperatures, etc.); however, those skilled in the art will account for some experimental error and deviation. Unless indicated otherwise, molecular weights are reported as average molecular weight.
Example 1
Inhibition of Xenograft Tissue Rejection Through Pre-Treatment with a Dextran Polymer
Dextran, derived from Leuconostoc mesenteroides , strain B512 (average Molecular Weight 500,000 Da) was used in the following studies. A dextran solution, suitable for administration to animals, was made by dissolving solid dextran in sterile deionized water (dH 2 O) to a final concentration of 10%.
For cellular implants into mice, human HT1080 spheroids expressing green fluorescent protein were used. These spheroids were prepared using the following method. Histone H2B-GFP, prepared as previously described (Kanda, et al., Curr. Biol. 26:377-85 (1998)), was subcloned into the LXRN retroviral vector (Clontech, Palo Alto Calif.). The resultant H2B-GFP LXRN vector was cotransfected with VSVG into GP-293 cells (Clontech) and viral supernatants harvested 48 hours post transaction. Retroviral supernatants were concentrated by centrifugation at 50,000 g and stored at −80° C. until use. HT1080 cells (obtained from ATCC) or IPSC (pancreatic beta stem cells (provided by Ixlon Biotechnology, Alachua, Fla.)) were transduced with VSVG pseudotyped H2BGFP LXRN virus stocks for 48 hours with 5 μg/ml polybrene and were selected in 300 μg/ml G418 for 2 weeks. Pooled cells that expressed H2BGFP, as determined by fluorescent microscopy and FACs analysis, were expanded and used for in vivo experiments. HT1080 cells were passaged in DMEM 4.5 g/L glucose supplemented with pyruvate, glutamine, non-essential amino acids, and gentamicin (50 μg/ml) and maintained in a humidified 5% CO 2 atmosphere at 37° C. Cells were routinely tested for mycoplasma contamination with the Genprobe mycoplasma detection kit. Suspensions of trypsinized monolayers were washed with fresh complete medium viability tested with trypan blue exclusion, and diluted to a final volume of 250,000 cells/ml. The cell suspensions were dispersed 100 ul/well into 96 well round bottom plates coated with 1.0% agarose for a liquid overlay. The spheroids were allowed to compact for 48 hours followed by washing in serum free media for implantation into mice bearing titanium chambers.
C57B1/6 mice were prepared by surgically implanting titanium chambers into a dorsal skinfold as described previously, (see, Lehr, et al., Am. J. Pathol. 143:1055-1062 (1993); Torres et. al., Microvascular Research 49:212-226 (1995)). In brief, male mice (25-35 g body weight) were anesthetized (7.3 mg ketamine hydrochloride and 2.3 mg xylazine /100 g body weight, i.p.) and placed on a heating pad. Two symmetrical titanium frames were implanted into a dorsal skinfold, so as to sandwich the extended double layer of skin. A 15 mm full thickness skin layer was excised. The underlying muscle (M. cutaneous max.) and subcutaneous tissues were covered with a glass cover slip incorporated in one of the frames.
After a recovery period of 2-5 days, the mice were divided into both treatment and control groups. A 200 μl injection of the sterile 10% dextran solution was administered to the treatment group intravenously through the tail vein 48 hours prior to spheroid implantation. Equivalent injections of dH 2 O were administered to control group mice. A second 200 μl injection of the sterile 10% dextran solution was administered to the treatment group 24 hours after the first injection, whereas the control group received dH 2 O. On the day of implantation, an equivalent number of HT1080 spheroid cells expressing green fluorescent protein were implanted into the titanium chambers of both the control and treatment group mice. Subsequent to spheroid implantation, and for the duration of the experiment, 100 μl of the 10% sterile dextran solution was administered to each mouse in the treatment group intravenously through the tail vein at 24 hour intervals. Equivalent injections of dH 2 O were administered to the control mice. Throughout the course of the experiment, the size of HT1080 cell xenografts were measured by fluorescent intravital microscopy. This microscopy was performed using a Mikron Instrument Microscope (Mikron Instrument, San Diego, Calif.) equipped with epi-illuminator and video-triggered stroboscope illumination from a xenon arc (MV-7600, EG&G, Salem, Mass.). A silicon intensified target camera (SIT68, Dage-MTI, Michigan City, Ind.) was attached to the microscope. A Hamamatsu image processor (Argus 20) with firmware version 2.50 (Hamamatsu Photonic System, USA) was used for image enhancement and to capture images to a computer. A Leitz PL1/0.04 objective was used to obtain an over-view of the chamber and for determination of graft size.
Statistical analysis was made using a statistical software package (SigmaStat, Jandel Scientific). Statistical analysis was made using both analysis of variance and multiple comparison tests. For all tests, p values smaller than 5% were considered significant. Data was presented as MEAN±STD.
FIG. 2 plots the survival of the HT1080 spheroid xenografts for both dextran-treated mice and the control group. For the mice treated with dextran, the size of the HT1080 xenograft increases throughout the course of the experiment. By the end of the experiment, on day 14, the size of the xenograft has more than doubled. By contrast, the xenografts in the control mice decrease throughout the course of the experiment and have been eliminated by day 14. These results indicate that pretreatment with 10% dextran solution for 48 hours prior to transplantation results in effective inhibition of xenograft rejection.
Example 2
Effects of the Route of Administration of the Dextran Polymer on Xenograft Survival
To examine the temporal and spatial dependence of the dextran polymer on graft survival, dextran was administered intraperitoneally (i.p.) verses intraveneously (i.v.). The methodology of Example 1 was used with the following modifications. C57B1/6 mice having implanted titanium chambers were divided into four groups. The first group was designated as the control group and received no treatment. The second group received 200 μl i.p. injections of the sterile 10% dextran solution every 24 hours beginning two days prior to spheroid implantation. On the day of spheroid implantation and thereafter, the injection volume was reduced to 100 μl. The third group of mice received 100 μl i.v. injections of the sterile 10% dextran solution every 24 hours beginning four days after spheroid implantation. The fourth group (designated the Re-Implant group) was comprised of mice that had rejected a spheroid xenograft that had been implanted 10 previously. This group received i.v. dextran treatments beginning six day prior to re-implantation of spheroids. On the first and second day of treatment, a 200 μl volume of the sterile dextran solution was administered. On each day thereafter, the volume was decreased to 100 μl. These 100 μl injections were continued throughout the course of the experiment.
FIG. 3 shows the xenograft survival over the 14 day course of the experiment for each group of mice. By day 14, every group has experienced a significant reduction in xenograft size. In contrast with the i.v. dextran pretreatments described in Example 1, i.p. administration of dextran beginning 48 hours prior to implantation (group 2) did not enhance the survival of xenografts. Similarly, xenograft survival was not enhanced by i.v. treatments commencing four days after spheroid implantation (group 3). This result suggests that the mechanism by which dextran acts is not through inhibition of the ability of T-cells to extravasate into the chamber.
FIG. 3 also shows that dextran pretreatment could not protect spheroids which had been implanted into mice that had previously rejected a spheroid graft (group 4). By day 10 of the experiment, the spheroid graft was eliminated. Accordingly, this result eliminates the possibility of direct T-cell inhibition as a mechanism of suppression.
Example 3
The Effect of Dextran Uptake on Antigen Presenting Cells
The uptake of dextran by APCs was shown by injecting mice with fluorescein isothiocyanate (FITC) labeled dextran then visualizing tissue sections by fluorescent microscopy. C57/B16 mice were divided into two groups. Mice in the first group received a 200 μl i.v. injection of a 2% FITG labeled dextran solution (average MW of dextran 500,000 Da). Twenty-four hours later, the animals were sacrificed and organ sections were whole mounted and imaged using fluorescent microscopy. Mice in the second group received a 200 μl i.v. injection of an unlabeled 10% dextran solution one daily for 48 hours. At the end of the 48 hour period, the mice were given a 200 μl i.v. injection of the 2% FITC labeled dextran solution. Twenty-four hours later, these animals were subjected to the same treatment as mice in the first group.
Analysis of the tissues of mice in the first group revealed macrophage-like cells taking up the labeled dextran polymer in all tissues examined including brain, lung, spleen, kidney, peritoneum, lymph-nodes, skin, and liver. Analysis of the tissues of mice in the second group revealed no labeling which indicated that saturation of these cells with the unlabeled polymer had occurred. The conclusion from these studies was that perturbation of antigen presenting cell function was the principal mechanism by which this poorly catabolized polymer blocked transplant rejection.
Example 4
Temporal Optimization of Dextran Administration for the Survival of Xenografts in Mice
To demonstrate the temporal effect of dextran administration on xenografts, the methodology of Example 1 was used with the following modifications. C57B1/6 mice having implanted titanium chambers were divided into three groups. The first group was designated as the control group and received no treatment. The second group received 200 μl i.v. injections of the sterile 10% dextran solution every 24 hours beginning two days prior to spheroid implantation. On the day of spheroid implantation and thereafter, the injection volume was reduced to 100 μl. The third group received a 200 μl i.v. injection of the sterile 10% dextran solution 24 hours prior to spheroid implantation. On the day of spheroid implantation and every 24 hours thereafter, 100 μl injections were given.
FIG. 4 shows the effect of the length of dextran pretreatment on the survival of xenografts. Twenty four hour pretreatment with dextran only slightly increases the survival of the xenograft relative to the control By contrast, when treatment is started 48 hours prior to spheroid implantation, the xenograft survival is greatly enhanced. The results presented in FIG. 4 together with those in Example 3 show that complete saturation of the APCs is required for effective inhibition of graft rejection.
Example 5
Inhibition of Allograft Stem Cell Rejection by Dextran Pretreatment
Allograft stem cells transplants were tested to examine if such cells would benefit from systemically administered poorly catabolized polymers. The methodology of Example 1 was used with the following modification. Beta stem cells from the pancreas derived from NOD mice stably transfected with green fluorescent protein, prepared as previously described (Ramiya et al, Nature Medicine 6:278-282 (2000)), were implanted into the chambers of C57BL/6 mice or Balb/c mice.
FIG. 5 plots the survival of beta stem cell grafts in C57BL/6 mice for both the control and treatment groups. A similar increase in graft size for both the control and dextran-treated mice is shown throughout the course of the experiment. These results indicate that systemic pretreatment with dextran had no significant effect on the growth of the beta stem cells spheroids that were grown as isografts in the chamber of C57BL/6 mice.
By contrast, a significant difference in graft survival between the control and treatment groups for Balb/c mice can be observed. FIG. 6 shows that beta stem cell allografts fail to survive in untreated control mice by the end of the 35 day experiment. The beta stem cell allografts of the dextran-treated mice, however, show significant increase in size over the course of the experiment with a greater than 40-fold increase on day 35. These results and those from the previous examples demonstrate that both allografts and xenografts are protected by pre-administration with poorly catabolized polymers.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit and scope of that which is described and claimed.
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Methods to prevent the rejection of immunogenic tissues in an animal by administering a non-immunogenic, poorly catabolized molecule in an amount sufficient to inhibit an immune response are described herein. Also described are compositions that are useful for inhibiting immune responses in animals that are recipients of cellular transplants. For example, these methods and compositions can be used to prevent the rejection of xenografted and allografted tissues in an animal.
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BACKGROUND OF THE INVENTION
This invention relates to medical diagnostic x-ray apparatus, particularly apparatus for performing angiography.
In angiography procedures it is frequently necessary to obtain simultaneous x-ray views of the blood vessels in two different directions, such as in the postero-anterior direction and in the lateral direction. Apparatus which permits postero-anterior views is shown in U.S. Ser. No. 202,094, filed by Stivender et al. on Oct. 31, 1980 now U.S. Pat. No. 4,358,856 and assigned to the owner of the present invention. That application is incorporated herein by reference in its entirety to explain the construction and operation of the L-U arm apparatus for taking such views.
Two approaches are currently used for taking simultaneous lateral views. In the first approach, an x-ray source hung from the ceiling is positioned on one side of the patient and a freestanding x-ray detection device is positioned on the other side of the patient. As is well known, the freestanding detector and its associated electrical cables prevent the physician from moving freely around the patient and can also interfere with the source or detector for taking postero-anterior views. Another deficiency of this apparatus is that the source and detector for lateral views must be aligned manually.
A second approach is shown in FIGS. 12 and 13, illustrating two prior art devices. In the device shown in FIG. 12, a single structural member 20 carries an x-ray source 22 and an electronic image intensifier 24 at its respective ends. Member 20 is supported by a brace 26 pivotally mounted to an overhead support 28 for rotating the pattern of radiation passing from source 22 to detector 24 about a vertical axis without disturbing the relative alignment of source and detector. In the embodiment shown in FIG. 13, source 22 and detector 24 are rigidly mounted to the respective ends of a rigid C-shaped member 30 received in a guide 32, which again is pivotally mounted to an overhead support 34. In this embodiment, member 30 can be rotated as before, or can be driven in either direction through guide 32 to rotate the pattern of x-rays passing between source 22 and detector 24 about the longitudinal axis of a patient.
The devices of FIGS. 12 and 13 seriously interfere with access to the patient by the physician, and when in motion can present a hazard to the patient and those working around the patient. Also, since in both prior art embodiments the mass of the x-ray tube and image intensifier is supported at a single point between them, support members 20 and 30 are prone to gravitational and inertial bending moments and oscillations which complicate the problem of aiming source 22 at detector 24. Furthermore, such devices can be disturbing to the patient, who is encircled by machinery. These structures also are difficult or impossible to move out of the way when they are not in use, as the entire assembly must be moved as a unit and cannot be retracted or collapsed to provide head room.
SUMMARY OF THE INVENTION
In accordance with the invention, an x-ray source is supported by a ceiling mounted carriage and telescoping hanger which permit the source to translate longitudinally, laterally, and vertically and to independently pivot about vertical and horizontal axes. An electronic image intensifier or other detector is supported in similar fashion by an independent carriage and telescoping hanger. When the x-ray source and image intensifier are to be used for conducting a lateral fluoroscopic examination, the respective carriages are coupled to a bridge member pivotally mounted to an overhead support.
The vertical positioning means for the respective hangers are linked when the source and detector are coupled to the bridge, so raising the source lowers the image intensifier, and vice versa. A mechanical linkage for moving the source and detector apart or together is coupled with the vertical positioning means so that, whether the central ray passing between the source and detector is disposed horizontally or not, the source and detector are always aimed at and diametrically opposed about an isocenter within the anatomy of interest. The pivoting of the source and detector about their horizontal longitudinal axes is correlated with the vertical positions of the source and detector on their hangers by electronic position sensing means which transmit signals indicating the relative elevation and pivotal positions of the source and detector.
As a result of the features described above, the source and detector are separable and can be retracted to the ceiling for compact storage when separated, and yet are mechanically linked when coupled to the bridge for tilting the central ray about vertical or longitudinal axes, permitting a wide selection of possible examination angles. The amount of equipment surrounding the patient is minimized, so access to the patient is maximized.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a perspective view of the present invention deployed in an examination room. A patient is shown positioned on an examination table and a known L-U arm assembly (40) is shown.
FIGS. 2 and 3 are diagrammatic rear elevational views of two positions of the structure shown in FIG. 1, illustrating the geometrical relations of the x-ray tube, detector, patient, and examination room according to the present invention.
FIG. 4 is a fragmentary bottom plan view of the structure shown in FIG. 1, illustrating the mechanism for linking the x-ray source and detector together. Covers are removed and some parts are shown in section.
FIG. 5 is an enlarged detail view of the central portion of the structure shown in FIG. 4.
FIG. 6 is an enlarged detail view of an outside portion of the structure shown in FIG. 4.
FIG. 7 is a fragmentary side elevational view of the structure shown in FIG. 4.
FIG. 8 is a rear elevational view of the x-ray tube hanger and carriage shown in FIG. 1, and is representative of the structure of the x-ray image intensifier hanger and carriage as well.
FIG. 9 is an inside elevational view of the structure shown in FIG. 8, with covers removed and the x-ray tube broken away.
FIG. 10 is an enlarged detail view of the lower end of the x-ray tube hanger shown in FIG. 8.
FIG. 11 is a top plan view, partly in section, of the structure shown in FIG. 10.
FIGS. 12 and 13 are schematic perspective views showing two prior art structures. These views have already been discussed in the preceding Background of the Invention section.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Although the disclosure hereof is detailed and exact to enable those skilled in the art to practice the invention, the physical embodiments herein disclosed merely exemplify the invention, which may be embodied in other specific structure. While the best known embodiment has been described, the details may be changed without departing from the invention, which is defined by the claims.
Referring first to FIG. 1, patient 34 is supported on an examination table 36 which is cantilevered with respect to its base 38 to permit the equipment to be positioned at various points with respect to the patient. An L-U arm x-ray apparatus 40 is supported by the floor of the room, and in this arrangement can be used for postero-anterior examination of the patient. A further description of apparatus 40 can be found in the patent application previously incorporated by reference. The illustrated examination room includes an overhead support 28, which in the illustrated embodiment is its ceiling.
An x-ray source 22 and an x-ray detector 24 (here, a low powered x-ray tube and an electronic image intensifier for fluorographic studies) are respectively supported by telescoping hangers 42, 44 having their respective upper ends 46, 48 secured to an x-ray source carriage 50 and x-ray detector carriage 52. The lower ends 54 and 56 of hangers 42 and 44 pivotally receive x-ray source 22 and image intensifier 24 so the latter elements can respectively rotate about an axis 58 (which is parallel to the longitudinal axis through patient 34 and passes through the focal spot of x-ray source 22) and an axis 60 which is parallel to axis 58.
Central ray 62 of the pattern of x-rays emitted from source 22 is aimed through an isocenter 64, as is the longitudinal axis 66 of image intensifier 24 (about which the x-ray pattern received and acted upon by image intensifier 24 is disposed). Source 22 and image intensifier 24 are supported adjacent to the respective lateral sides of patient 34.
Carriage 50 is pivotally mounted to a roller truck 68 which is captured by parallel arms 70 and 72 of a lateral track member 74 to permit lateral travel of carriage 50 and rotation of the carriage about a vertical axis. Lateral track member 74 is suspended from a pair of roller trucks such as 76 which travel on parallel, longitudinally disposed tracks such as 78 mounted to overhead support 28 for permitting track member 74, and thus roller track 68 and carriage 50, to travel longitudinally. This system provides direct support for x-ray source 22, and since hanger 42 is substantially vertical it has substantially no bending moment due to gravity.
Carriage 52 similarly is pivotally suspended from roller truck 80, lateral track member 82, and roller trucks secured to member 82 for traveling on tracks 84 and 86 mounted to overhead support 28.
Although independently supported, carriages 50 and 52 can be coupled to a bridge member 88 pivotally secured to overhead support 28 for rotation about a vertical axis passing through isocenter 64. The coupling sites are first and second coupling means generally indicated by reference characters 90 and 92. As will be seen, each coupling means includes male and female members which are coupled as shown in FIG. 1 to locate the carriages and uncoupled when the carriages are to be separated. When the couplings are separated the x-ray source and detector can be independently moved, and can even be pushed into different corners of the examination room for storage. The x-ray source can also be used independently of the image intensifier when uncoupled. For example, L-U arm 40 can be pivoted 90 degrees about its floor pivot, so x-ray source 22 can be aimed at a auxiliary detector mounted to arm 40 (as disclosed in the previously incorporated patent application).
Electric power and control cable bundles 94 and 96, containing conductors for providing electric power to x-ray source 22 and detector 24 and for operating the invention, are routed from source 22 and detector 24 to the respective carriages 50 and 52, and from there in helical coils supported by slides 98 carried in tracks such as 86 to a remote connection point (not shown).
FIGS. 2 and 3 show several geometric relationships which are maintained by the illustrated embodiment. B is the distance from pivot axis 58 of x-ray source 22 to isocenter 64; C is the distance from pivot axis 60 to isocenter 64; D is the horizontal component of B and lies along a lateral axis 120 through isocenter 64; E is the horizontal component of C and also lies on axis 120; F is the vertical component of B; G is the vertical component of C; h is the angle between B and D; and i is the angle between C and E. Isocenter 64 is always stationary. B and C are always equal, and do not change for any position of the apparatus. F and h are respectively equal to G and i, and they all vary between zero (as in FIG. 3) and a positive value (as in FIG. 2). Thus, source 22 and image intensifier 24 are always diametrically opposed through isocenter 64 when coupled by bridge 88, and the source to image distance remains constant for any value of h and i. Central ray 62 and longitudinal axis 66 are always directed through isocenter 64 and are collinear. Finally, the entire assembly is rotatable as a rigid unit about a vertical axis 122 through isocenter 64.
To maintain the equality of F and G, source 22 and detector 24 are mechanically linked by bridge 88, carriages 50 and 52, and hangers 42 and 44 so raising either source 22 or detector 24 lowers the other by an equal amount. To keep B and C constant during such vertical travel, carriages 50 and 52 are translated toward bridge 88 when F and G are increased and away from bridge 88 when F and G are decreased. At the same time, microprocessor controlled servomechanisms aim source 22 and detector 24 toward isocenter 64 by varying h and i. The details of these mechanisms are shown in FIGS. 4-11.
In the illustrated embodiment, image intensifier 24 can translate along its longitudinal axis 66 with respect to hanger 44 to vary the isocenter to image distance without disturbing the foregoing relationships. This additional capability allows the magnification of the image to be varied without changing the other relationships just described.
Referring now to FIGS. 4-7, bridge 88 comprises a cross shaped horizontally disposed housing 130 mounted to overhead support 28 (FIG. 1) for pivoting about vertical axis 122 (which passes through isocenter 64). Housing 130 supports coaxial splined shafts 132 and 134. The inboard end 136 of shaft 132 is carried by ball bearings 138 and 140 mounted to a truck 142 having rollers such as 144, 146, 148, and 150 which permit slight vertical translation of truck 142 within housing 130. The outboard end of shaft 132 is a probe 152 for being received in the bore 154 of a tubular member 156. Member 156 is supported partially within x-ray source carriage 50 by rotation and thrust bearings such as 158, 160. A first coupling member 164, here a male member, is splined to and slidable along shaft 132. Second coupling member 166 is a female member secured to member 156 to receive first coupling member 164. Second coupling member 166 includes a dog 168 for being received in a bore 170 in first coupling member 164 so when the coupling members are coupled they rotate together. Coupling members 164 and 166 are seated together when coupled by a ball detent mechanism. First coupling member 164 is linked to a slide 172 which is slidably carried on splined shaft 132. Tubular member 156 includes a coaxial bevel gear 174 that meshes with a bevel gear 176 secured to a shaft 178 to which a power take-off cable drum 180 is fixed. The cable drum shaft is rotatably secured to fixed members 182 and 184 of carriage 50 by thrust and rotation bearings.
A counterpoise drum 185 is also mounted to carriage 50. A flat spiral torsion spring (not shown) has its respective ends secured to drum 185 and its supports for exerting a counterclockwise (as seen in FIG. 8) torque on drum 185. A cable 186 is wound on counterpoise drum 185, reeved about power take-off drum 180 and about an idler pulley 188, and has a vertical run 189 best seen in FIG. 8. The lower end 190 of run 189 is anchored to the lower arm of hanger 42. Winding cable 186 onto drum 185 by turning drum 180 with motor 303 of the coupling drive raises source 22 and collapses hanger 42, while rotating drum 180 in the other direction extends hanger 42 and thereby lowers source 22.
An encoder 192 is driven by an encoder cable 194 which is wound about another drum (not shown) fixed and coaxial with respect to power take-off drum 180. Cable 194 is run through direction changing block 196, and run vertically downward to an anchor 198 fixed to the lower arm of hanger 42. Encoder 192 is thus enabled to transmit a signal corresponding to the vertical position of source 22.
For each of the structures identified by reference numerals 136 through 198 there is a corresponding structure associated with splined shaft 134, carriage 52, and hanger 44, although some of the latter elements are not separately illustrated. Reference characters for the illustrated features are as follows: inboard end 210 of shaft 134; bearings 212 and 214; truck 216; rollers 218, 220, 222, and 224; tubular member 226; coupling members 228 and 230; bevel gears 232 and 234; cable drum 236 and cable 238.
A chain drive is provided to couple splined shafts 132 and 134 so they will rotate in the same direction at the same speed. Referring to FIGS. 4, 5, and 7, sprockets 250 and 252 are keyed to the inboard ends of splined shafts 132 and 134, sprockets 254 and 256 are keyed to a shaft 258 secured to bridge 88 for rotation, and chain tension adjusting sprockets 260 and 262 are rotatably and slidably carried on bridge 88. A first endless chain 264, trained about sprockets 250 and 254 and under sprocket 260, transmits the rotation of shaft 134 to shaft 258 (and vice versa), and an identical chain 266 transmits the rotation of shaft 132 to shaft 258 (and vice versa). When the carriages are coupled to the bridge, cable 186 is wound by drum 180 at the same rate that cable 220 is unwound by drum 218, and vice versa. The vertical travel of source 22 is thus equal and opposite to the vertical travel of image intensifier 24 when the assembly is coupled together as shown in the Figures.
The following mechanism is provided for spreading carriages 50 and 52 apart or drawing them together as required to keep the source to image distance constant despite relative vertical travel of the source and detector. A guide 270 is disposed perpendicularly to shafts 132 and 134 and is secured to bridge 88 by fasteners such as 272. A slide 276 is slidably carried on guide 270, and link arms 278 and 280 are each secured at one end by a pivot pin 282 to slide 276. The other ends of link arms 278 and 280 are secured by pivots 284 to the outer races of rotation bearings such as 286 carried on the respective slides such as 172. Slide 276 is driven by an endless drive chain 288 having its respective ends reeved about a sprocket 290 keyed to shaft 258 and a sprocket 292 rotatably carried by shaft 294 journaled in bearings 296 and 298 at the remote end of bridge 88. Referring to FIG. 7, a link 300 (which includes a chain tension adjustment) secures chain 288 to slide 276. Chain 288 is also reeved about an idler sprocket 301 rotatably secured to bridge 88 and about a drive sprocket 302 driven by a reversible servomotor 303. When sprocket 302 is driven one way by servomotor 303, slide 276 and link arms 278 and 280 move toward the position shown in phantom in FIG. 4, x-ray source 22 is raised, image intensifier 24 is lowered, and carriages 50 and 52 are spread apart as h and i decrease. Reversing the servomotor causes slide 276 and link arms 278 and 280 to approach the positions shown in full lines in FIG. 4, source 22 to be lowered, image intensifier 24 to be raised, and carriages 50 and 52 to be drawn together as h and i increase. When slide 276 is in the position shown in phantom in FIG. 4, that is, nearest shafts 132 and 134, link arms 278 and 280 and the carriages are spread to their maximum separation and source 22 and detector 24 are level with isocenter 64. The drive just described also includes a potentiometer 314 which senses and transmits the approximate rotational position of shaft 258, which in turn is directly related to the exact vertical positions of the x-ray source and detector (provided by their respective encoders such as 192) and the separation between coupled carriages 50 and 52.
FIGS. 8, 9, 10, and 11 illustrate details of hanger 42 and carriage 50. (Although hanger 44, carriage 52 and associated structures are not specifically shown, they are identical to the corresponding structures of hanger 42 and carriage 50 as described herein.) In addition to parts previously identified in the preceding disclosure, FIGS. 8 and 9 show that roller truck 68 includes roller assemblies such as 320, 322, and 324, of which rollers 320 and 324 are carried in track 72 and roller 322 is carried in track 70. Hanger 42 comprises telescoping segments 332, 334, 336, and 338, the latter secured to a horizontally and obliquely extending arm 340 supporting a pivot shaft 342 which is coaxial with the focal point of x-ray tube 22. A sheave 344 rotatably secured to shaft 342 receives a cable 346 having its respective ends 347 secured to sheave 344 as shown in FIG. 10. Cable 346 is driven by a sheave 348 mounted on a pivot shaft 350 rotatably carried by a frame 352 secured to arm 340. Sheave 348 is connected via a clutch and gear reduction 354 (shown in FIG. 11) to a reversible stepper motor 356 mounted to frame 352. Frame 352 can be made slidable with respect to arm 340 by loosening its fastenings for adjusting the tension of cable 346, and an adjustment mechanism 358 bearing between arm 340 and frame 352 is provided for that purpose.
FIG. 11 shows the details of clutch and gear reduction 354. Cable 346 has been removed in FIG. 11 for greater clarity of illustration. Stepper motor 356 has an output shaft 360 secured to a sheave 361 which is connected via a drive belt (not shown, for clarity) to a sheave 363 secured to an input shaft 364 of a high ratio in line gear reduction set. Shaft 364 is carried by bearings 366, 368 secured to a fixed member 370. Member 370 is secured by fasteners 372, 374 to a member 376 of frame 352. Input shaft 364 is keyed to wave generator 378--a ball bearing having an elliptical inner race 380 and a flexible outer race 382. Race 382 is pressed into flexible spline ring 384, which has 240 teeth on its outside edge. Spline ring 384 is received within a fixed ring gear 386, having 242 internal teeth and secured by fasteners 388 to fixed member 370, and also within a rotating ring gear 390 having 240 internal teeth and secured by fasteners 392 to a disc 293 secured to pivot shaft 350. Rotation of elliptical race 380 flexes the teeth of diametrically opposed portions of spline ring 384 outwardly to sequentially mesh with the adjacent teeth of ring gears 386 and 390. Ring gear 386 is fixed and has two more teeth than spline 384, therefore permitting spline 384 to make two revolutions contrary to the rotation of inner race 380 for each 240 revolutions of inner race 380. Ring gear 390, which has the same number of teeth as spline 384, rotates at the same rate as spline 384. The resulting drive ratio is thus 240:2, or 120:1.
Pivot shaft 350 is supported by bearing 394 (secured to stationary member 396) and drives sheave 348 via a normally engaged clutch generally indicated at 398 (shown disengaged). Clutch 398 comprises a ferromagnetic plunger 400 splined to and axially slidable to a slight degree along pivot shaft 350; first and second clutch plates 402 and 404, the former secured to pivot shaft 350 by a retainer 406, the latter secured nonrotatably but axially movable relative to magnetic coil housing 408 (which in turn is secured to sheave 348); compression coil springs 412 carried on slidable guide shafts 410 and bearing between coil housing 408 and second clutch plate 404; and a conductive coil shown schematically at 414, having terminals 416 and 418 for being connected to a source of D.C. power. Bearing 419 transmits axial thrust but no torque between plunger 400 and clutch plate 404.
Clutch 398 is engaged when no power is fed to coil 414 because springs 412 urge clutch plate 402 against clutch plate 404. Because of the high gear reduction between shaft 360 and sheave 348, if stepper motor 356 is not energized and clutch 398 is engaged x-ray source 22 will maintain its pivotal position. By energizing coil 414, which counteracts the bias of springs 412 and thereby disengages the clutch plates, sheave 348, and thus sheave 344, are free to rotate to allow manual pivoting of the x-ray source.
The pivotal position of x-ray tube 22 is transmitted by a position encoder 420 via a timing pulley 422, timing belt 424, and a timing pulley 426 mounted on pivot shaft 342.
The x-ray image intensifier 24 includes essentially identical structure, including position encoders for hanger length and pivotal position, a gear reduction, a clutch, and frame elements, to allow it to be manually positioned when the clutch is disengaged and automatically positioned when the clutch is engaged, the pivotal position being indicated by the position encoder regardless of the condition of the clutch.
When the hangers are not in use, couplings 90 and 92 are uncoupled and hangers 46 and 48 are usually fully retracted. The apparatus can be moved into position and coupled for conducting a lateral x-ray study as follows. A central microprocessor control first reads the position signal transmitted by the encoder associated with the length of hanger 44, and operates servomotor 303 for the bridge coupling mechanism to rotate coupling member 228 to the correct position for coupling with coupling member 230. Second, the image intensifier is manually extended or retracted to about the correct height and pivoted (with its clutch released) to approximately the correct position for the desired study. Servomotor 303 automatically compensates for any vertical travel of hanger 44 as already explained. Third, the image intensifier 24 is docked to bridge 88 and coupling members 228 and 230 are joined. Fourth, the microprocessor reads the position signals transmitted by the encoders associated with vertical travel of hanger 44 and pivotal travel of image intensifier, and operates the image intensifier pivoting stepping motor as necessary to precisely aim the longitudinal axis of image intensifier 24 through isocenter.
Next, the x-ray source 22 and associated hanger 42 and carriage 50 are manually operated to bring source 22 to approximately the proper height, coupling members 164 and 166 are juxtaposed, the height of source 22 is adjusted as necessary to line up the coupling members, and they are coupled. The microprocessor control is instructed to read the position signals transmitted by position encoders 192 and 420 to determine the height and pivotal position of x-ray source 22, and (with clutch 398 engaged) servomotor 356 is actuated as necessary to correlate the pivotal position of source 22 with its height, thereby aiming its central ray through isocenter.
Although a preferred mode of operation is described, it will be appreciated that other modes of operation could be practiced with the same apparatus within the scope of the present invention.
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Means for coupling an independently suspended medical x-ray source and detector for lateral fluorographic studies such as angiography. When coupled, the x-ray source and detector move vertically in opposite directions, move horizontally toward or away from each other, and pivot about horizontal axes so the distances between the focal spot and isocenter of examination and between the isocenter and image each remain constant, and so the central ray of the source coincides with the central ray of the detector. The bridge also rotates to rotate the entire assembly about a vertical axis passing through the isocenter.
The x-ray source and detector are independently hung from the ceiling to support them directly above their centers of weight, eliminating the bending moments and oscillation which are inherent features of prior C-arm structures.
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CROSS REFERENCE TO RELATED PATENT APPLICATION
This application is a continuation-in-part of commonly assigned, copending U.S. patent application Ser. No. 305,884 filed Sept. 28, 1981 now U.S. Pat. No. 4,346,241.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the recovery of oxygenated organic compounds from dilute aqueous solutions by liquid-liquid extraction employing a variety of liquid extraction media, and is especially applicable to recovering and concentrating ethanol present in the dilute aqueous solutions obtained by fermentation.
2. Description of the Prior Art
With the ever-increasing depletion of economically recoverable petroleum reserves, the production of ethanol from vegetative sources as a partial or complete replacement for conventional fossil-based liquid fuels becomes more attractive. In some areas, the economic and technical feasibility of using a 90% unleaded gasoline-10% anhydrous ethanol blend ("gasohol") has shown encouraging results. According to a recent study, gasohol powered automobiles have averaged a 5% reduction in fuel compared to unleaded gasoline powered vehicles and have emitted one-third less carbon monoxide than the latter. In addition to offering promise as a practical and efficient fuel, biomass-derived ethanol in large quantities and at a competitive price has the potential in some areas for replacing certain petroleum-based chemical feedstocks. Thus, for example, ethanol can be catalytically dehydrated to ethylene, one of the most important of all chemical raw materials both in terms of quantity consumed and versatility in product synthesis.
The various operations in processes for obtaining ethanol from such recurring sources as cellulose, cane sugar, amylaceous grains and tubers, e.g., the separation of starch granules from non-carbohydrate plant matter and other extraneous substances, the chemical and/or enzymatic hydrolysis of starch to fermentable sugar (liquefaction and saccharification), the fermentation of sugar to a dilute solution of ethanol ("beer") and the separation and concentration of the ethanol by distillation, have been modified in numerous ways to achieve improvements in product yield, production rates and so forth (see, for example, U.S. Pat. No. 3,236,740 and the booklet "Industrial Alcohol by Continuous Fermentation and Vacuum Distillation With Low Energy Consumption," of Chemapec, Inc., Woodbury, N.Y.). For ethanol to realize its vast potential as a partial or total substitute for petroleum fuels or as a substitute chemical feedstock, it is necessary that the manufacturing process be as efficient in the use of energy and raw materials as possible so as to maximize the energy return for the amount of ethanol and enhance the standing of the ethanol as an economically viable replacement for petroleum based raw materials. To date, however, relatively little concern has been given to the energy and raw material requirements for manufacturing ethanol from biomass and consequently, little effort has been made to minimize the thermal expenditure and waste of raw materials incurred in carrying out any of the aforesaid discrete operations involved in the manufacture of ethanol from vegetative sources.
Recovery of fermentation ethanol by distillation accounts for a large amount of the overall energy requirements for conversion of biomass to concentrated ethanol. Roddy, "Distribution of Ethanol-Water Mixtures to Organic Liquids," Ind. Eng. Process Des. Dev., 1981, 20, 104-108, proposes the use of organic solvent extraction followed by gas stripping of ethanol from the organic phase as a sustitute for distillation in alcohol separation and concentration. According to this publication, the hydrocarbons as a class are poor extractants for ethanol but tend to give the highest separation factors because of their even poorer solvent properties for water. A variety of ethanol extractants were evaluated including cyclohexane, benzene, toluene, xylene, ethylbenzene, chloroform, 1-octanol, 2-ethyl-1-butanol, n-butyl acetate and tri-n-butyl phosphate, and their distribution coefficients K (i.e., the value obtained by dividing the concentration of ethanol in the organic layer by the concentration of ethanol in the aqueous layer) were measured. Roddy discloses that the highest distribution coefficient (designated by the author as D EtoH ) was 6.9×10 -1 (measured at 25° C.) which was obtained for 2-ethyl-1-butanol. The only nitrogen-containing extractants evaluated by Roddy, Amberlite XLA3, a primary amine from Rohm and Haas, and Adogens 364 and 464, tertiary and quaternary amines from Ashland Chem., had much lower distribution coefficients, measuring 4.4×10 -3 , 1.7×10 -2 and 4.8×10 -1 respectively.
Similarly, other oxygenated organic materials are obtained in chemical, biochemical and fermentation processes in dilute aqueous solutions and their efficient recovery is desirable to a commercial process. Exemplary of such oxygenated organic materials comprise alcohols, aldehydes, ketones, ethers, acids, esters and the like.
SUMMARY OF THE INVENTION
For convenience, the following description of the invention will relate principally to the recovery of ethanol from dilute aqueous solutions. It will be understood however, that the instant process is equally applicable to the recovery of other dilute aqueous solutions of oxygenated organic materials comprising alcohols, aldehydes, ketones, ethers, acids and esters, and that such embodiments are also embraced within the scope of the present invention. Broadly stated, the dilute aqueous solutions contain, by weight, about 0.1% to 30%, or higher, and usually about 1% to 20%, e.g., 1% to 10%, of the oxygenated organic material. Exemplary materials are C 1 -C 10 or higher oxygenated organic materials with the preferred materials being C 1 -C 8 or C 1 -C 4 carbon containing compounds.
Illustrative oxygenated organic materials are alcohols such as methanol, ethanol, n-propanol, n-butanol, ethylene glycol, glycerin, etc.; aldehydes such as acetaldehyde, propionaldehyde; etc.; ketones such as acetone, methyl ethyl ketone, etc.; ethers such as dimethyl ether, diethyl ether, etc.; acids such as acetic, propionic, butyric, etc.; and esters such as methyl acetate, ethyl acetate, vinyl acetate, methyl propionate, etc.
In accordance with the present invention, ethanol present in dilute aqueous solution is recovered therefrom in more concentrated form by contacting said dilute aqueous ethanol solution with at least one inert extractant which is liquid at ambient temperature and pressure, said extractant being selected from the group consisting of unsubstituted and substituted cyclic secondary amines and unsubstituted and substituted aromatic cyclic amines having a distribution coefficient at ambient temperature and pressure of at least about 0.70.
The use of an ethanol extractant of the aforesaid type combined with removal of the ethanol from the extractant by distillation to provide anhydrous ethanol as more fully described herein can reduce the heat inputs required to obtain anhydrous ethanol from dilute solutions by substantial amounts. For example, the heat inputs required for recovery of anhydrous ethanol from 4.5% and 8% by weight aqueous ethanol solutions employing conventional distillation procedures will frequently average about 25,000 and 13,000 BTU/gal., respectively. However, employing 5,6,7,8-tetrahydroquinoline (THQ) which has a distribution coefficient at ambient temperature and pressure of about 1.05 as extractant, the heat inputs can be reduced to 15,590 and 11,540 BTU/gal., respectively. In the case of fermentation ethanol, the additional capital investment required to implement the liquid-liquid extraction process of the present invention can be more than offset by employing a single stage, in contrast to a multistage, fermentation system since the thermal savings which can be realized by the practice of this invention will often be far more pronounced with aqueous ethanol feeds of relatively low concentration, e.g., from about 2-6 % by weight, than with feeds of relatively high ethanol concentration, e.g., from about 6-12% by weight.
While the process of this invention is especially advantageous when applied to the recovery and concentration of ethanol produced by fermentation, the process is similarly beneficial when applied to dilute aqueous ethanol streams obtained from other processes, e.g., from the catalytic hydration of ethylene.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the solubility of water in a number of extractants herein at temperatures of from 0° C. to 80° C.
FIG. 2A is a schematic diagram of a multistage, countercurrent liquid-liquid ethanol extraction process in accordance with one embodiment of the present invention and FIG. 2B is a schematic diagram of a distillation process which is integrated with the extraction process of FIG. 1A to provide substantially anhydrous ethanol.
FIG. 3 is a schematic diagram illustrating the process herein on a laboratory scale.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The ethanol extractant herein is selected from among any of the inert, normally liquid unsubstituted and substituted liquid secondary amines, and unsubstituted and substituted aromatic cyclic amines having a distribution coefficient under ambient conditions of at least about 0.70. The distribution coefficient, K EtOH , of the extraction solvents herein were measured at ambient temperature and pressure and are calculated by dividing the weight concentration of ethanol in the organic, i.e., extractant, layer by the concentration of ethanol in the aqueous layer. As a class, the cyclic and heterocyclic amines are excellent extractants for ethanol possibly due to the high affinity of the nitrogen for the hydroxylic hydrogen of the ethanol. Whatever, in fact, the explanation for this behavior may be, it is possible employing routine procedures to identify many more members of this class of materials besides those specifically identified hereinafter which possess a K EtOH value of at least about 0.70 at ambient temperature and pressure. Extractants having a K EtOH value of at least about 0.90 and more preferably, above about 1.0, are especially advantageous for use in the present invention. Specific examples of useful extractants, together with their distribution coefficients, are set forth in Table I as follows:
TABLE I______________________________________ DistributionExtractant Coefficient______________________________________1,2,3,4-tetrahydroisoquinoline 1.002-aza-5,5-bicyclospiroundecane 1.16quinoline 1.12isoquinoline 0.922,3-cyclopentenopyridine 1.075,6,7,8-tetrahydroquinoline 1.052,3-cycloheptenopyridine 0.764-isopropylpyridine 1.24-n-propylpyridine 1.02-n-propylpyridine 0.974-(3-pentyl)pyridine 0.82______________________________________
Based purely on operational considerations, it is preferred to employ an extractant having the highest distribution coefficient. In practice, however, the selection of extractant will ordinarily take cost into consideration so that the choice of extractant for a given facility at a given time will represent a balance between the technical effectiveness of the material and its cost.
Another approach toward the selection of extractant makes use of the separation factor (S.F.) which is the ratio of the partition coefficient for K EtOH , as previously defined, to water, K H .sbsb.2 O (i.e., the water concentration in the solvent layer divided by the water concentration in the aqueous layer). With the extractants herein, the solubility of water decreases with increasing temperature so K H .sbsb.2 O also decreases. A value of S.F. greater than about 1.0 indicates that the extractant will preferentially dissolve ethanol thereby enriching it relative to water. For a given K EtOH , the larger the S.F. the more effective the extractant in the process of this invention. It is preferred to employ an extractant having an S.F. of at least about 5.0 at 21° C., and more preferably, an S.F. of at least about 20 at 21° C., in the practice of this invention.
The solubility of water in the most effective extractants (quinoline, 2-aza-5,5-bicyclospiroundecane, 4-isopropylpyridine, and tetrohydroquinoline) was experimentally determined over the range 0° C. to 80° C. by titrating water into a stirred sample of the extractant. The end point was considered to be a stable cloud point. In all cases the solubility of water decreased with increasing temperature.
The curves plotted from the solubility data are shown in FIG. 1. The equations for these curves, derived by linear regression, are:
______________________________________quinoline W = 21.1e.sup.-0.0082T, (r = 0.968)2-aza-5,5-bicyclospiroundecane W = 23.7e.sup.-0.031T, (r = .978)4-isopropylpyridine W = 17e.sup.-0.015T, (r = .970)5,6,7,8-tetrahydroquinoline W = 20.8e.sup.-0.02T, (r = .942______________________________________ where: W = weight % of water T = temperature in °C. r = correlation coefficient
Extractions were made at 60° C. to experimentally determine the temperature effect on the K EtOH and S.F. for quinoline, 5,6,7,8-tetrahydroquinoline, and 2-aza-5,5-bicyclospiroundecane. As shown in Table II below, both K EtOH and S.F. increased with temperature while K H .sbsb.2 O decreased. The concentration of ethanol relative to water in the raffinate was enriched from 4.5% to 65% with decahydroquinoline.
TABLE II______________________________________EFFECT OF TEMPERATURE ON EXTRACTION Wt. % EtOH in Extract Temp. (RelativeSolvent °C. K.sub.EtOH K.sub.H.sbsb.2.sub.O S.F. to H.sub.2 O)______________________________________Quinoline 21 1.00.sup.1 0.17 5.8 20 60 1.12 0.15 7.5 262-Aza-5,5-bicyclo- 21 0.88 0.13 6.8 25spiroundecane 60 0.97 .043 23 54Decahydroquinoline 21 0.94 .047 20 54 60 1.04 .025 42 60______________________________________ .sup.1 Value obtained in multistage extraction.
In addition to these extractions, another series of extractions were carried out at 85° C. and 100° C. Table III below summarizes the observed data.
TABLE III______________________________________EFFECT OF TEMPERATURE ON EXTRACTION Wt. % EtOH in Extract Temp. (RelativeSolvent °C. K.sub.EtOH K.sub.H.sbsb.2.sub.O S.F. to H.sub.2 O)______________________________________Quinoline 21 1.00 0.17 5.8 20 60 1.12 0.15 7.5 26 85 1.20 0.14 8.8 28 100 1.22 0.13 9.4 282-Aza-5,5-bicyclo- 21 0.88 0.13 6.8 25spiroundecane 60 0.97 0.043 23 54 85 0.88 0.021 42 655,6,7,8-tetra- 21 1.05 0.20 5.3 20hydroquinoline 85 1.30 0.072 18 41 100 1.32 0.056 24 49Decahydroquinoline 21 0.94 0.047 20 54 60 1.04 0.025 42 65 85 0.92 0.017 54 711,9-Octahydro- 21 1.15 0.37 3.1 11quinoline 85 1.44 0.059 24 49______________________________________
As shown in these data, the highest S.F. was 54, obtained at 85° C. with decahydroquinoline which enriched the ethanol from 4.5% to 71% relative to water. With the solvents tested, high S.F. values resulted more from the decrease in K H .sbsb.2 O with increasing temperature rather than an increase in K EtOH .
The highest K EtOH was 1.44, obtained with 1,9-octahydroquinoline at 85° C., the K EtOH's for decahydroquinoline and 2-aza-5,5-bicyclospiroundecane peaked at 60° C. and decreased at higher temperatures. Both quinoline and tetrahydroquinoline K EtOH's increased with temperature until 85° C. but had the same values at 100° C. It was not determined if maximum K EtOH's existed between 85° C. and 100° C.
The K EtOH for delta-1,9-octahydroquinoline, a by-product of the synthesis of decahydroquinoline, was not determined at 100° C. because of insufficient material. The solubility of water in delta-1,9-octahydroquinoline was determined from 0° C. to 80° C. The equation derived is:
W=4.9e.sup.-0.029T,(r=0.997)
where:
W=weight % of H 2 O
T=Temperature in °C.
r=correlation coefficient.
In general, the extraction will be carried out at about the temperature of the aqueous ethanol feed or at elevated temperatures approaching the boiling point of the ethanol-extractant mixture. It is, of course, recognized that while elevated temperatures favor greater extraction levels, such can be achieved only with the input of heat which may or may not be available at relatively low cost depending upon the design of other elements of biomass ethanol system.
The quantities of extractant employed herein can vary widely with the extraction effectiveness of a particular solvent, its cost, the volume of dilute aqueous ethanol being processed, flow rates, the number of extraction stages, contact times and similar factors being taken into consideration when determined the optimum quantity of extractant for a given facility.
In accordance with FIG. 2A, an aqueous fermentation ethanol feed containing from about 4.5-8 weight percent ethanol is continuously introduced into the bottom of a third rotating disk contactor extraction column 20 through line 11 while 5,6,7,8-tetrahydroquinoline (THQ) extractant is continuously introduced into the top of column 10 through line 12 via pump 13 to effect counter-current extraction of ethanol contained in the feed stream. The ethanol-containing THQ discharged from the bottom of column 10 through line 14 is then introduced via pump 15 into the top of a second rotating disk contactor extraction column 16 to accomplish still further extraction of ethanol with the raffinate discharged from the top of column 20 being delivered by gravity to the bottom of column 16 through line 17. The sequence of extraction is repeated for a third time with the ethanol-containing THQ discharged from the bottom of column 16 through line 18 being introduced via pump 19 to the top of third rotating disk contactor extraction column 20 and the raffinate discharged from the top of column 16 being delivered by gravity to the bottom of column 10 through line 21. The ethanol-containing THQ extractant discharged from the bottom of column 20 through line 22 is then sent by pump 23 to distillation as hereinafter described in FIG. 2B for separation of the ethanol and THQ and recycle of the latter. The extract from column 20 contains ethanol in a concentration of from about 25-35 weight percent relative to water (depending on feed stream concentration and extraction temperature). The raffinate phase from column 10 which contains a small amount of extractant, is introduced through line 24 into the top of extractant recovery column 25 continuously supplied at the bottom thereof with xylene or other THQ extractant through line 44. The aqueous bottoms from column 25 are either discharged to waste through line 26, or, if the residual amounts of solvent therein have no appreciably detrimental affect on fermentation, are recycled. The THQ/xylene mixture discharged from the top of column 25 through line 27 is delivered via pump 28 through line 29 and through condenser 30 to partially condense the overheads from solvent recovery fractionation column 32, through preheater 31 and thereafter into said fractionation column 32 driven with steam supplied through reboiler shell 33. The bottoms recovered from fractionator column 32, containing THQ, are sent via pump 34 through line 35 and through preheater 31 giving up a portion of the thermal values therein to the THQ/ethane entering fractionation column 32 and thereafter to rectifier column feed preheater 50 whose operation is hereinafter described in FIG. 2B. The xylene vapor overheads from column 32 passing through line 36 are partially condensed by the THQ/ethanol/xylene mixture passing through condensor 30, a portion of the condensed xylene in overheads accumulator 37 being recycled through line 38 by pump 39 to the top of column 32 to serve as reflux and the remainder of the partial xylene condensate being recycled through line 40 by pump 41 to be combined with the balance of the xylene passing through line 42 and which has been condensed in overhead condenser 43. The combined xylene streams in line 44 are passed through recycle cooler 45 and thereafter into the bottom of column 25 to effect further recovery of THQ/ethanol from the raffinate phase. THQ recycle extractant from the distillation process described in FIG. 2B passing through line 46 is cooled by solvent recycle cooler 47 and is decanted in solvent recycle decanter 48 to remove excess water therein, the aqueous phase being recycled to distillation through line 49 and the THQ phase being recycled through line 12 via pump 13 to the top of first rotating disk contactor extraction column 10 for use in extracting fresh aqueous ethanol feed.
In accordance with FIG. 2B, ethanol-rich THQ extractant in line 22 (i.e., the organic phase from third rotating disk contactor extraction column 20 of FIG. 2A) is passed through rectifier feed preheater 50 where it picks up thermal values from the THQ bottoms forced from rectifier column 51 through line 52 by pump 53 and THQ bottoms forced from fractionation column 32 of FIG. 2A through line 35 by pump 34 thereof. The combined THQ streams are recycled through line 46 of FIG. 2A as previously described. The preheated THQ ethanol stream introduced through line 22 into rectifier column 51 operated at or about atmospheric pressure is heated therein by recovered steam provided to rectifier reboiler shell 54 and steam provided to rectifier trim reboiler shell 55 as demand requires. The THQ bottoms are recovered therefrom through line 52 as previously described and the ethanol vapor overheads are recovered through line 56. Passing through rectifier condenser 57, the condensate enters rectifier reflux drum 58 and is discharged therefrom by pump 59 through line 60 with part of the ethanol being conveyed to storage through line 62 and part being returned as reflux through line 61. A side draw stream withdrawn from rectifier column 51 through line 63 and containing fusel oil is combined with recycle water passing through line 49 of FIG. 2A and after passing through side draw cooler 64 is introduced into side draw decanter 65. The fusel oil phase in decanter 65 is recovered through line 66 and is sent by pump 67 either to separate storage or to storage with the ethanol passing through line 62. The aqueous phase recovered from decanter 65 through line 68 is recycled by pump 69, together with the THQ/ethanol stream passing through line 22, into rectifier column 51. The aqueous ethanol (about 94 weight percent ethanol) recovered from rectifier 51 through line 70 is forced by pump 71 through anhydrous column preheater 72 and into anhydrous column 73 wherein azeotropic distillation is carried out, preferably at substantially superatmospheric pressure, e.g., from about 60 to about 150 psig, and more preferably, from about 80 to about 130 psig. By operating anhydrous column 73 at significantly elevated levels of pressure, a sufficient amount of heat is recoverable from this column to supply a good part, if not all, of the thermal operating requirements of rectifying column 51. Heat is supplied to anhydrous column 73 by liquid recirculating through reboiler 74 supplied with steam. Part of the vapor overhead (azeotropeforming agent, ethanol and water) passing from anhydrous column 73 through line 75 is conveyed through line 76 giving up heat in reboiler shell 54 to rectifying column liquid recirculating therethrough. The condensed liquid resulting from the passage of anhydrous column overheads through reboiler shell 54 enters drum 77 and is delivered therefrom through line 78 by pump 79 to the top of anhydrous decanter column 80. Another part of the vapor passing from anhydrous column 73 through line 75 is conveyed through line 81 through condenser 82 with the condensate entering decanter 80. Start-up azeotrope-forming agent can be supplied to the system at any convenient point such as through line 83 to decanter 80. The phase in decanter 80 which is rich in azeotrope forming agent is conveyed through line 84 by pump 85 to the top of anhydrous column 73 to provide reflux liquid. The water-rich phase in decanter 80 containing a small amount of ethanol passes through line 86 and through cooler 87 into water stripper column 88 which is driven by steam supplied to reboiler shell 96.
Vapor overheads from water stripper column 88, consisting of azeotrope forming agents, are conveyed through line 89 and passing through stripper condenser 90, are condensed, the condensate passing into stripper column reflux drum 91. Part of the condensed azeotrope-forming agent is returned to column 88 through line 92 to serve as reflux with the remainder of the azeotrope-forming agent being delivered through line 93 by pump 94 to decanter 80. The bottoms from column 88, consisting of clean water, are discharged therefrom by pump 97 through line 98, either to be discarded or recycled as desired.
While any of the azeotrope-forming agents heretofore employed for the anhydrous distillation of ethanol, e.g., benzene, toluene, etc., can be used herein with good results, it is preferred to employ cyclohexane for this purpose especially when anhydrous column 73 is operated under pressure. In the past, it has been proposed to carry out anhydrous distillation of ethanol at elevated pressure employing diethyl ether an an entraining agent. (Moeller et al., Industrial Engineering Chemistry, Vol. 43, No. 3, pp. 711-717 (1951); Wentworth et al., Trans. Am. Inst. Chem. Engrs., Vol. 39, pp. 565-578 (1943) and Vol. 36, pp. 785-799 (1940)). However diethyl ether has numerous drawbacks compared to cyclohexane for this purpose. For one thing, much higher anhydrous column operating pressures would be required in order to provide sufficient heat to run a rectifying column when working with diethyl ether. For another, diethyl ether is more hazardous than cyclohexane and reasons of safety alone militate against its use. Moreover, ether gives inferior separation between ethanol and water compared to that provided by cyclohexane.
EXAMPLE I
In the schematic diagram illustrated in FIG. 3, a twelve-stage countercurrent extraction system with quinoline (practical grade, saturated with water before use to minimize sorption of water from the aqueous phase) as extractant was employed in a laboratory scale demonstration of the present invention applied to a beer containing about 8 percent ethanol by weight. Equal volumes (100 ml) of beer and extractant were introduced to the system at room temperature.
Start-up required batchwise initiation of the stages to the process as shown in FIG. 3. Feed and solvent were introduced into funnel 6, stage 6 of the extraction system. The funnel was then vigorously shaken and allowed to settle for 10-15 minutes. When phase separation was complete, the extract phase (lower layer) was drawn off and transferred to funnel 7 and the raffinate phase (upper layer) to funnel 5. Fresh extractant was then added to the raffinate in funnel 5 and fresh feed added to the extract in funnel 7. After agitation and settling, the extract from funnel 7 was drawn off and transferred to funnel 8 and the raffinate to funnel 6 in B. The extract from funnel 5 was drawn off and transferred into funnel 6 and the raffinate to funnel 4. Fresh solvent was then added to funnel 4 and fresh feed to funnel 8. This procedure was followed until all twelve funnels were introduced into the system (C, D, E and F). The extract phase from stage N would transfer into stage N+1, and the raffinate phase from stage N would transfer into stage N-1, thereby effecting a countercurrent extraction system. When the system was complete, fresh feed was added to funnel 12 and a raffinate withdrawn from the system from funnel 1 as shown in F. After separation took place, fresh solvent was added to funnel 1 and an extract was withdrawn from the system from funnel 12 as shown in G, such constituting one full cycle of the system.
After 11 full cycles had been completed, the raffinates from cycles 9, 10, and 11 were analyzed for ethanol content by gas-liquid chromatography. While steady-state had not been established in 11 cycles, such was achieved in 15 cycles. Twenty-five ml extract and raffinate samples were then taken from each funnel for analysis. The results showed that 95% of the ethanol present in the feed was recovered in the extract. The complete results are reported in Table IV below. The raffinate samples were analyzed by gas-liquid chromatography using propanol as an internal standard. Since the extract analysis did not use an internal standard, each sample was analyzed three or more times and an average value calculated for ethanol content. This procedure resulted in an error of ±9% with a certainty of 95%. A material balance shows that the final extract was 109.5 ml and the final raffinate 90.5 ml.
TABLE IV______________________________________TWELVE STAGE COUNTERCURRENT EXTRACTION OFETHANOL WITH SATURATED QUINOLINE SOLVENT Raffinate ExtractStage ETOH Conc. mmol/ml. ETOH Conc. mmol/ml.______________________________________1 .091 .0992 .188 .2013 .287 .3134 .394 .4265 .512 .5746 .620 .6437 .736 .7758 .837 .9299 .960 1.02510 1.088 1.17511 1.259 1.34012 1.331 1.480______________________________________
EXAMPLE II
Similarly as shown hereinabove in TABLES I and II, extractions were performed on dilute aqueous solutions of acetone, n-propanol, n-butanol, acetic acid and butyric acid and the results are reported in TABLE V. Each solvent was saturated with water prior to the extraction and the extractions were performed at room temperature by mixing 10 milliliters (mls.) of the water-saturated solvent with 10 mls. of the aqueous solution of the oxygenated organic material.
TABLE V______________________________________ Initial Aqueous Oxygenated Concentra-Solvent Organic Material tion (wt. %) K.sup.1 K.sub.H.sbsb.2.sub.O S.F.______________________________________Quinoline n-butanol 5 5.8 0.19 31 n-propanol 10 1.9 0.2 9.5 acetone 10 0.8 0.2 4.0 acetic acid 10 1.6 0.2 8.0 butyric acid 10 8.7 0.16 541,2,3,4 n-butanol 5 4.7 0.38 12tetrahydro- n-propanol 10 2.0 0.40 5.0isoquinoline acetone 10 1.2 0.45 2.74-n-propyl- n-butanol 5 22 0.15 150pyridine n-propanol 10 2.9 0.15 19 acetone 10 1.2 0.15 8______________________________________ .sup.1 K value for the oxygenated organic material.
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A thermally efficient process for recovering an oxygenated organic material, such as ethanol, present in dilute aqueous solution is disclosed which comprises contacting said dilute aqueous solution with at least one inert extractant which is liquid at ambient temperature and pressure, said extractant being selected from the group consisting of unsubstituted and substituted cyclic secondary amines and unsubstituted and substituted aromatic cyclic amines having a distribution coefficient of at least about 0.70 or a separation factor of at least about 1.0. The invention further provides a process for obtaining substantially anhydrous oxygenated organic material from a dilute aqueous solution thereof in which the stream is subjected to liquid-liquid extraction to provide an oxygenated organic material poor raffinate phase and an oxygenated organic material rich extract phase, the oxygenated organic material present in said latter phase is concentrated in a rectifying column to provide an aqueous oxygenated organic material of high concentration and, if desired or necessary, the concentrated stream is azeotropically distilled in an anhydrous column operated under substantially superatmospheric pressure with thermal values recovered from said anhydrous column being used to satisfy part of all of the thermal operating requirements of the rectifying column.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from United Kingdom Application 0905027.9 filed Mar. 24, 2009, which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] This invention relates to flying apparatus and a method of use thereof.
[0003] Although the following description refers almost exclusively to hovering flying apparatus in the form of a toy quadcopter or quadrotor, it will be appreciated by persons skilled in the art that the present invention can relate to any suitable flying apparatus with any number of rotors, whether it be a toy or full size flying apparatus.
[0004] It is known to provide flying or hovering apparatus in the form of a quadcopter or quadrotor. This is a type of aircraft which is lifted and propelled by four sets of rotors. Control of motion of the aircraft can be achieved by varying the relative speed of each rotor to change the thrust and torque produced by each rotor.
SUMMARY OF THE INVENTION
[0005] An example of a conventional quadrotor aircraft 2 is shown with reference to FIG. 1 . The aircraft 2 includes a central body 4 with four elongate arms 6 , 8 , 10 , 12 protruding outwardly therefrom to form a substantially cruciform shaped frame when viewed in plan. A rotor 14 is provided at the free end of each arm 6 - 12 and each rotor 14 is capable of undergoing rotational movement about a substantially vertical axis 16 . Oppositely mounted rotors 14 are rotatable in the same direction and adjacently mounted rotors 14 are rotatable in opposite directions. Thus, two rotors move in a clockwise direction 18 and two rotors move in an anti-clockwise direction 20 in use of the aircraft. The torque reactions provided by driving the rotors balance, and the aircraft does not tend to spin about its central axis. Control electronics (not shown) are located in central body 4 and are typically controlled remotely via a remote control handset. A motor is associated with each rotor to allow independent control of the same.
[0006] The above described arrangement allows movement of the aircraft 2 to be controlled in three axes, by varying the speed of each rotor 14 . For example, to pitch the aircraft forwards, the speed of the front rotor is reduced and the speed of the rear rotor is increased. To roll the aircraft to the right, the speed of the right rotor is reduced and the speed of the left rotor is increased. To yaw the aircraft to the right, the speed of the front and rear rotors are reduced and the speed of the left and right rotors are increased. This creates an imbalance in the torque reaction which causes the aircraft to rotate but does not create a tilt force and does not affect the overall lift of the aircraft.
[0007] Although the above described aircraft works in principle, most designs are small in size and result in rapid responses to control inputs, thereby making it difficult for a user to control. In order to overcome this problem, electronic motion sensors or gyroscopes are used to detect rotation in each of the three axes of movement (pitch, roll and yaw). These sensors provide direct negative feedback to the rotor motors to dampen the aircraft's rotational motion and help control the stability of the same. The sensors typically form part of the electronic control system mounted in the central body of the aircraft.
[0008] It is an aim of the present invention to provide flying apparatus which provides an improved level of stability.
[0009] It is a further aim of the present invention to provide a method of using flying apparatus having an improved level of stability.
[0010] According to a first aspect of the present invention there is provided flying apparatus, said apparatus including a housing with two or more rotor means associated therewith, said rotor means arranged to rotate about substantially parallel axes in use and wherein one or more vanes are provided with said apparatus to help stabilize the apparatus in use.
[0011] The one or more vanes perform two main stabilizing functions; firstly they provide drag to prevent tilt of the apparatus and secondly the drag provides damping against oscillation movement of the apparatus.
[0012] Preferably the two or more rotor means are located a spaced distance apart and arranged so as to balance the apparatus in use. For example, each rotor means can be located equal spaced distances apart from each other. The rotor means are preferably located in substantially the same vertical position with respect to the apparatus.
[0013] Preferably the two or more rotor means are arranged a pre-determined radial distance from a central body or point of said apparatus. The pre-determined radial distance is preferably substantially the same for each rotor means.
[0014] Preferably the two or more rotor means are located on or associated with a frame of said apparatus. Further preferably each rotor is located at or adjacent a peripheral edge or corner of said frame.
[0015] In one embodiment the frame is in the form of a cruciform shape when viewed in plan. For example, a plurality of elongate arms can protrude outwardly from a central body or point and rotor means can be provided at or adjacent a free end of each of said elongate arms.
[0016] In one embodiment the frame is in the form of a square shape when viewed in plan and each rotor means can be provided at or adjacent a corner of said frame.
[0017] Preferably the frame means are substantially rigid in form.
[0018] In one embodiment the apparatus includes at least three rotor means and in a preferred embodiment the apparatus includes four rotor means.
[0019] Preferably each rotor means is rotatable about a substantially vertical axis in use.
[0020] Preferably each rotor means includes two or more rotor blades and preferably said rotor blades are arranged to rotate about a substantially vertical axis.
[0021] Preferably the one or more vanes are located above, and preferably a spaced distance above the rotor means of the apparatus.
[0022] Preferably the number of vanes provided on the apparatus equals the number of rotor means provided on said apparatus.
[0023] In one embodiment the vanes are orientated substantially parallel to the frame members associated with each of the rotor means.
[0024] Preferably each vane is substantially flat or in a sheet like form. The vane is arranged in a substantially vertical plane or in a plane substantially parallel to the axis about which said rotor means rotate in use.
[0025] In one embodiment each vane has a first end which is joined to or adjacent a first end of a further vane, and a second free end.
[0026] In one embodiment the first ends of each vane are located at or adjacent a substantially central axis of the apparatus and protrude outwardly or radially from said central axis.
[0027] In one embodiment each vane spans substantially the entire diameter of the apparatus, housing or frame. If two or more vanes are provided, the vanes are typically arranged to be substantially equal distance apart from each other or in such orientation to allow balancing of the apparatus in use. For example, two vanes can be used which slot together to form a cruciform shape when viewed in plan. One or more slits or slots can be defined in the vanes to allow slotting of the same together.
[0028] The size, shape and/or height of the one or more vanes can be adjusted to alter the stability of the apparatus as required.
[0029] The vanes can be integrally formed, attached or detachably attached to the apparatus, frame or housing. The attachment means for allowing the attachment or detachable attachment of the one or more vanes include any or any combination of adhesive, welding, one or more clips, slots, hook and loop fastening, screws, inter-engaging means, friction fit and/or the like.
[0030] Preferably control means are contained in, provided on or associated with the housing. The control means allow control of the rotor means and preferably the rotor means are each independently controlled via the control means.
[0031] Preferably the flying apparatus is controlled remotely via remote control means, such as for example by a remote controlled handset operable by a user. The control means can communicate with the remote controlled handset via infra red, radio frequency and/or the like. Suitable transmitter and/or receiving means can be associated with the apparatus and/or the remote controlled handset as required to allow control signals to be passed between the handset and the flying apparatus.
[0032] Preferably the control means includes one or more motion sensors. Yet further preferably the motion sensors are capable of detecting pitch, roll and/or yaw of the apparatus.
[0033] In one embodiment of the present invention the rotor means are located at or adjacent a base of the apparatus or below said housing.
[0034] In one embodiment one or more support feet can be provided on or associated with a base of said apparatus, frame or housing to support the apparatus when on a surface, such as for example in an “out of use” position. The support feet typically protrude below the rotor means.
[0035] In one embodiment one or more wheels, rollers or other suitable movement means are provided at or adjacent the base of the apparatus to allow the apparatus to be moved across a surface, such as a ground or floor surface in use.
[0036] Preferably the flying apparatus is in the form of a hovering or non-spinning apparatus and yet further preferably the flying apparatus is in the form of a toy for use by a child or adult.
[0037] Preferably the flying apparatus is in the form of a quadrotor.
[0038] Preferably suitable drive means are provided to allow driving of the rotation of the rotor means. The drive means can include a motor, suitable gearing and/or the like.
[0039] Preferably power means are provided to allow powering of the drive means. The power means can include a mains power supply, battery power, rechargeable battery power and/or the like.
[0040] The two or more rotor means can be arranged in substantially the same horizontal plane, in an adjacent or side by side manner or can be arranged in a stacked manner, such as coaxially, with one rotor means located above or below a further rotor means.
[0041] According to a second aspect of the present invention there is provided a method of using flying apparatus, said apparatus including a housing with two or more rotor means associated therewith, said method including the step of rotating said rotor means about substantially parallel axes and wherein one or more vanes are provided with said apparatus to help stabilize the apparatus in use.
[0042] According to further aspects of the present invention there is provided a quadrotor and a method of using a quadrotor.
BRIEF DESCRIPTION OF THE INVENTION
[0043] An embodiment of the present invention will now be described with reference to the following figures, wherein:
[0044] FIG. 1 shows an example of a prior art quadrotor aircraft in plan view;
[0045] FIG. 2 is a perspective view of a quadrotor aircraft according to an embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0046] Referring to FIG. 2 , there is illustrated a quadrotor 100 according to an embodiment of the present invention. The quadrotor 100 has a central body portion 102 containing electronic control means. Frame means in the form of four elongate arm members 104 protrude radially outwardly from body portion 102 . Each arm member is spaced equidistance apart and is of substantially equal length. The arm members are arranged to form a substantially cruciform shape when viewed in plan from above.
[0047] Rotor means in the form of four rotors 106 are located at the free ends of each arm member 104 . Each rotor 106 includes two rotary blades 108 , 110 rotatable about a substantially vertical axis. A motor 114 is associated with each rotor 106 at the free end of each arm 104 . The motors 114 are connected or communicate with the electronic control means provided in the central body portion 102 to allow control of the rotation of each of the rotors. The rotors 106 are operable using the control means and a remote control handset in a similar manner to the prior art device described in FIG. 1 .
[0048] Support feet 112 are provided to protrude from a base of body portion 102 for supporting the quadrotor on a ground surface, such as for example a substantially horizontal surface in use.
[0049] In accordance with the present invention, there are provided four stabilizing vane members 116 to help stabilize the quadrotor in use. Each vane member 116 has a first end 118 which is attached to a first end of an adjacent vane member at a substantially central vertical axis of the apparatus, and a second end 120 which is located adjacent rotor 106 at a peripheral edge of the apparatus.
[0050] Each vane member 116 is in a sheet like form with a height substantially greater than a width thereof in the illustrated example. The vane members 116 can be any suitable shape but in the illustrated example the top section or top edge of the vane member is substantially curved or convexed in shape.
[0051] The vane members can be substantially rigid or flexible in form providing they offer some degree of stability to the apparatus.
[0052] Each vane member typically protrudes radially from a central point of the apparatus and, in the illustrated example, are substantially parallel to the frame members 104 .
[0053] Four separate vane members can be provided or two vane members can be provided which span between two oppositely located rotors.
[0054] The vane members help the apparatus to be automatically self leveling in use. The vane members are located above the rotors and extend above the top of the body portion where the electronic control means are located. The vane members are thin and formed from light weight material. The vane members provide a large amount of aerodynamic drag during horizontal movement of the apparatus. For example, the vane members arranged between the front and rear of the apparatus provide drag against sideways movement of the apparatus in use. The vane members arranged between the left and right of the apparatus provide drag against fore-aft movement of the apparatus in use.
[0055] The vanes perform two main functions. Firstly, because the vanes are mounted at the top of the apparatus, the drag generated by the vanes tends to tilt the apparatus in the opposite direction to any horizontal movement undertaken by the apparatus. This provides a form of negative feedback, tending to keep the apparatus in a substantially horizontal, stationary hover. Secondly, the drag provides damping against substantially horizontal movement undertaken by the apparatus. This is important, otherwise the feedback affect from the vanes would cause the apparatus to oscillate back and forth in a pendulum type of motion. Although the two functions are provided by a pair of vanes or four vanes, the magnitude of the effect can be varied independently by changing the size of the vanes (which adjusts both effects together) and/or the height of the vanes (which alters the amount of tilt feedback but not the amount of horizontal damping).
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Flying apparatus is provided including a housing with two or more rotor means associated therewith. The rotor means are arranged to rotate about substantially parallel axes in use. One or more vanes are provided with said apparatus to help stabilize the apparatus in use.
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CROSS-REFERENCE TO RELATED APPLICATIONS
Not Applicable
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable.
APPENDIX
Not Applicable.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention pertains to vibratory devices of the type used in the bulk material handling industry. More particularly, this invention pertains to a rotary vibratory device having repositionable eccentric weights and to methods for extending the useful life of such rotary vibratory devices.
2. General Background
Vibratory devices are used throughout the bulk material handling industry for various purposes. Vibratory devices are often attached to bulk material transfer chutes and bulk material storage hoppers to prevent bulk material from clinging to the walls of such chutes and hoppers. Vibratory devices are also utilized on sifting screens to prevent larger material from clogging the sifting screens and to speed the flow of material passing through the screens.
A common type of vibratory device is the rotary vibratory motor, wherein eccentric weights are rotationally driven by, and rotate about, a shaft and thereby create a oscillating forces. Other types of vibratory devices include, but are not limited to, acoustical vibration devices, air driven rotary vibrators, and linear vibrators. The present invention pertains specifically to the rotary vibratory device wherein on or more eccentric weight is rotationally driven by a shaft (hereafter referred to simple as a rotary vibratory device).
In rotatory vibratory devices, the forces generating in by the rotating eccentric weights are transmitted to the motor housing via the bearings that support the rotor shaft. In view of the eccentricity of the weights, the bearing forces acting on the rotary shaft peak on the side of the bearing shaft that is closest to the center of mass of the eccentric weights, while the opposite side of the rotor shaft sees little, if any, bearing load. As a result, the portion of the bearing surface of the shaft closest to the center of mass of the eccentric weights wears at the greatest rate.
SUMMARY OF THE INVENTION
The inventors of the present invention have appreciated that the useful life of rotary vibratory devices can be extended by periodically altering the location of greatest bearing surface wear rate circumferentially about the shaft. The inventors have also developed rotary vibratory devices that are configured and adapted to allow for periodically altering the location of greatest bearing surface wear rate with minimal effort.
In one aspect of the invention, a method of extending the service life of an eccentric weight vibratory device comprises accessing a vibratory device. The vibratory device comprises a rotor and first and second eccentric weights. The rotor has a central shaft about which the rotor is configured to rotate. The shaft has opposite first and second end portions. The first eccentric weight is initially attached to the first end portion of the shaft in a manner such that the center of the mass of the first eccentric weight is offset in a first radial direction from the shaft. The second eccentric weight is initially attached to the second end portion of the shaft in a manner such that the center of the mass of the second eccentric weight is also offset in the first radial direction from the shaft of the rotor. The method also comprises reorienting the first eccentric weight relative to the shaft in a manner such that the center of the mass of the first eccentric weight is offset in a second radial direction from the shaft, and reorienting the second eccentric weight relative to the shaft in a manner such that the center of the mass of the second eccentric weight is offset in the second radial direction from the shaft. By performing these steps, the location of greatest bearing surface wear rate on the shaft is circumferentially relocated about the shaft. As such, the service life of an eccentric weight vibratory device is thereby extended.
In another aspect of the invention, a vibratory device comprises a rotor having a shaft. The shaft has a shaft axis about which the rotor is configured to rotate. The shaft also comprises a first end portion having a plurality of keyways that are spaced circumferentially about the shaft axis relative to each other. An eccentric weight is mounted on the first end portion of the shaft. The eccentric weight has a center of mass that is offset from the shaft axis and has an opening through which the first end portion of the shaft extends. The opening comprises a keyway. The vibratory device also comprises a key. The key is positioned between one of the keyways of the shaft and the keyway of the eccentric weight in a manner such that the first eccentric weight is not able to rotate relative to the shaft about the shaft axis.
Further features and advantages of the present invention, as well as the operation of the invention, are described in detail below with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts a perspective view of a rotary vibratory device.
FIG. 2 depicts the vibratory device of FIG. 1 , with its end caps removed for servicing.
FIG. 3 depicts an initial configuration of a plurality of eccentric weights mounted on the shaft of the rotor of the vibratory device shown in FIGS. 1 and 2 .
FIG. 4 depicts another view of the rotor and weights in the initial configuration.
FIG. 5 depicts the rotor and weights from the same viewing angle as shown in FIG. 4 , but is shown with the weights disengaged from the shaft keys.
FIG. 6 depicts the rotor and weights from the same viewing angle as shown in FIGS. 4 and 5 , and shows the weights and shaft keys repositioned about the rotor shaft ninety degrees.
FIG. 7 depicts the rotor and weights from the same viewing angle as shown in FIGS. 4-6 , and shows the weights reengaged with the shaft keys after having been rotationally repositioned.
Reference numerals in the written specification and in the drawing figures indicate corresponding items.
DETAILED DESCRIPTION
A preferred embodiment of a rotary vibratory device in accordance with the present invention is shown in FIGS. 1 and 2 . The vibratory device 10 comprises an outer housing 12 having removable end caps 14 . Internally, the vibratory device 10 comprises a rotor 16 having a shaft 18 . A plurality of eccentric weights 20 are mounted on the shaft 18 of the rotor 16 for rotation therewith.
Although some rotary vibratory devices may include only one eccentric weight or have eccentric weights only on one end of rotor shaft, the preferred embodiment of a rotary vibratory device 10 in accordance with the present invention comprises at least one eccentric weight 20 at each of the opposite end portions 22 of the rotor's shaft 18 . Preferably the weights 20 are balanced such that the forces acting on each end portion of the shaft 18 equal each other and act in the same direction.
As is shown most clearly in FIGS. 3-7 , the rotor 16 comprises an armature 24 that is centrally positioned on the shaft 18 . The rotor 16 also comprises a plurality of bearings 26 that attach the rotor to the housing 12 for rotation (and transmit the vibrational forces to the housing). Each of the opposite end portions 22 of the shaft 18 comprises an anular groove that is configured to receive a removable retaining ring 28 . Additionally, each of the opposite end portions 22 of the shaft 18 comprises a plurality of keyways 30 that are circumferentially spaced from each other about the shaft. Preferably, each of the opposite end portions 22 of the shaft 18 comprises two or more axially oriented keyways 30 that are evenly spaced apart from each other about the shaft. The keyways 30 are preferably simple slots milled into the shaft 18 . The eccentric weights 20 attached to the end portions 22 of the shaft include outboard eccentric weights 32 and inboard eccentric weights 34 . Each end portion 22 of the rotor shaft 18 has one outboard weight 32 and one inboard eccentric weight 34 attached thereto. Each of the eccentric weights 20 comprises a mounting hole 36 that is offset from the center of mass of the eccentric weight and that is dimensioned to fit snugly around the shaft 18 . Each of the eccentric weights 20 also comprises slit 38 that extends into the mounting hole 36 and that allows the eccentric weight to be tightly clamped to the shaft via a bolt 40 . Moreover, the mounting hole 36 of at least each of the inboard eccentric weights 34 also comprises an axially extending keyway 42 that is preferably milled into the weight. The rotor 16 further comprises a key 44 and preferably a pair of adjustment guides 46 .
The eccentric weights 20 of the vibratory device 10 are initially axially and rotationally locked to the shaft 18 of the rotor 16 in an initial position. The keyway 42 of each of the inboard eccentric weights 34 is aligned with one of the keyways 30 of the shaft 18 and one of the keys 44 is positioned between said keyways in a manner rotationally locking the weight to the shaft. Given that each end portion 22 of the shaft 18 preferable has at least two keyways 30 , each inboard eccentric weight 34 is positionable in alternative positions relative to the shaft. As mentioned above, a bolt 40 also clamps each of the eccentric weights to the shaft 18 in a manner such that the weights cannot rotate or axially slide relative to the shaft. Thus, the keys 44 and keyways 30 , 42 serve primarily to index the inboard eccentric weights 34 and to ensure that they are aligned with each other. The outboard eccentric weights 32 may or may not be aligned with the inboard eccentric weights 34 . In other words, the center of mass of the outboard eccentric weights 32 may be offset from the axis of rotation of the shaft 18 in a different direction than is the center of mass of the inboard eccentric weights 34 . Unlike the inboard eccentric weights 34 , the orientation angle of the outboard eccentric weights 32 relative to the shaft is infinitely variable since the outboard eccentric weights and the shaft are not keyed to each other. It should be appreciated that the rotational position of the outboard eccentric weights 32 relative to the inboard eccentric weights 34 determines the combined center of mass of the weights and the more out of alignment the inboard and outboard weights are, the closer the combined center of mass is to the axis about which the shaft 18 rotates. The radial distance between the combined center of mass of the eccentric weights 20 and the shaft axis determines the amplitude of the vibrations created by the vibratory device 10 at any given revolutions per minute.
It should be appreciated that as the rotary vibratory device 10 operates, the greatest bearing load on the bearing surfaces of the shaft 18 (which engage the bearings 26 of the rotor 16 ) occur on the side of the shaft facing the center of mass of the eccentric weights 20 . As such, those portions of the shaft 18 wear faster than the other portions of the bearing surfaces of the shaft. Eventually the wear exceeds an acceptable amount. At that point or time, the vibratory device 10 can be serviced to change the location of the greatest bearing load on the bearing surfaces of the shaft 18 . To do this, a technician removes the end caps 14 of the vibratory device's 10 housing 12 to expose the eccentric weights 20 (see FIG. 2 ). The technician then loosens the bolts 40 that secure the eccentric weights 20 to the end portions 22 of the shaft 18 of the rotor 20 . Thereafter the technician axially slides the eccentric weights 20 away from armature 24 of the rotor 16 to disengage the keyways 42 of the inboard eccentric weights 34 from the shaft keys 44 , as is shown in FIG. 5 (note: although FIGS. 3-7 show the rotor removed from the housing 12 , it is shown that way for clarity and the rotor remains in the housing during servicing). Preferably the end portions 22 of the shaft 18 are long enough such that the weights 20 can be axially slide on the shaft enough to disengage the keyways 42 of the inboard eccentric weights 34 from the shaft keys 44 without removing the weights from the shaft (as is shown on the right side of the rotor 16 in FIG. 5 ). To this end, the retaining rings 28 serve as end stops for preventing the eccentric weights 20 from sliding off of the rotor's 16 shaft 18 . With the shaft keys 44 exposed, the technician can remove the keys and place them in another set of the plurality of keyways 30 of the shaft, and then rotate the inboard eccentric weights 34 relative to the shaft 18 until the keyways 42 of the inboard eccentric weights are once again aligned with the shaft keys (as shown in FIG. 6 ). Following that, the eccentric weights 20 are pushed axially inboard such that the shaft keys 44 lie between the keyways of the shaft 30 and the keyways 42 of the inboard eccentric weights 34 (as shown in FIG. 7 ). The outboard eccentric weights 32 are also rotated into their proper orientation relative to the inboard weights 34 , using the adjustment guides (which include graduated markings showing the relative angles between the inboard and outboard weights).
Following the servicing of the vibratory device 10 , the device will operate in the same manner that it did before servicing, except that the location of the greatest bearing load on the bearing surfaces of the shaft 18 will be different from before. Although the shaft 18 of the vibratory device 10 is shown in the figures having four keyways 30 at each of its opposite end portions 22 , preferably it only has two keyways at each end. Having only two keyways 30 at each end of the shaft 18 ensures that there won't be any overlap in the wear area on the inner bearing race of the shaft from one position to the next. Thus, the vibratory device 10 can continue to operate without risking failure. Moreover, if more than two keyways 30 are provided at each end portion 22 of the shaft 18 , the servicing procedure can be performed additional times (each time placing the key 44 in a yet to be used keyway 30 of the shaft 18 ). Thus, using the present invention, the useful life of the vibratory device 10 can be extended by at least twice that of standard vibratory device. It should also be appreciated that the key 44 and keyways 30 , 42 of the vibratory device 10 are configured and adapted to assist a technician in rotationally indexing the eccentric weights 20 and are not the primary means for torsionally locking the eccentric weights to the shaft.
In view of the foregoing, it should be appreciated that the invention has several advantages over the prior art.
As various modifications could be made in the constructions and methods herein described and illustrated without departing from the scope of the invention, it is intended that all matter contained in the foregoing description or shown in the accompanying drawings shall be interpreted as illustrative rather than limiting. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims appended hereto and their equivalents.
It should also be understood that when introducing elements of the present invention in the claims or in the above description of exemplary embodiments of the invention, the terms “comprising,” “including,” and “having” are intended to be open-ended and mean that there may be additional elements other than the listed elements. Additionally, the term “portion” should be construed as meaning some or all of the item or element that it qualifies. Moreover, use of identifiers such as first, second, and third should not be construed in a manner imposing any relative position or time sequence between limitations. Still further, the order in which the steps of any method claim that follows are presented should not be construed in a manner limiting the order in which such steps must be performed, unless such and order is inherent.
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A method comprises accessing a vibratory device having a rotor and first and second eccentric weights. The first weight is initially attached to the rotor's shaft in a manner such that its center of the mass is offset from the shaft in a first radial direction. The second weight is initially attached to the shaft in a manner such that its center of the mass is also offset in the first radial direction. The method further comprises reorienting the first and second weights relative to the shaft in a manner such that their centers of the mass are offset in a second radial direction. By performing these steps, the location of greatest bearing surface wear rate on the shaft is circumferentially relocated about the shaft. As such, the service life of an eccentric weight vibratory device is thereby extended.
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FIELD OF THE INVENTION
This invention relates to a novel integrated hydroconversion process for converting heavy hydrocarbon feeds containing vacuum residue and converting and reducing impurities in the straight run and conversion product vacuum gas oil liquids. This is accomplished by utilizing two residue ebullated-bed hydroconversion reaction stages, two vapor-liquid separators, and at least two additional distillate ebullated-bed hydrocracking/hydrotreating reaction stages.
In a two-stage residue hydroconversion reactor system, the atmospheric or vacuum residue feed and hydrogen react with a catalyst in the first residue hydroconversion stage to produce lighter hydrocarbons. The stage one effluent is thereafter separated in an interstage separator which separates the effluent into a liquid phase and a vapor phase.
The liquid phase from this interstage separator is then fed to the second residue hydroconversion reaction stage for additional conversion and impurity reduction. The resulting mixed-phase effluent product from this second stage is sent to a second high-pressure separator with the liquid product sent to product separation.
The overhead vapor from the first stage (interstage separator) and from the second vapor liquid separator contain significant unreacted hydrogen and are thereafter sent to separate distillate ebullated-bed reactors for conversion and hydrotreatment of the diesel and vacuum gas oils contained in these streams. These downstream ebullated-bed hydrogenating/hydrotreating reactors are called distillate ebullated-bed reactors to distinguish them from the upstream system. Additional feedstocks to these distillate ebullated-bed reactors could include straight run vacuum gas oil, cracked material from other processing units, and recovered diesel and VGO from the second-stage residue ebullated-bed hydrocracking product.
BACKGROUND OF THE INVENTION
Hydrocarbon compounds are useful for a number of purposes. In particular, hydrocarbon compounds are useful, inter alia, as fuels, solvents, degreasers, cleaning agents, and polymer precursors. The most important source of hydrocarbon compounds is petroleum crude oil. Refining of crude oil into separate hydrocarbon compound fractions is a well-known processing technique that can be accomplished by a variety of different methods.
Crude oils range widely in their composition and physical and chemical properties. Crude oil with a similar mix of physical and chemical characteristics, usually produced from a given reservoir, field or sometimes even a region, constitutes a crude oil “stream.” Most simply, crude oils are classified by their density and sulfur content. Less dense (or “lighter”) crudes generally have a higher share of light hydrocarbons—higher value products—that can be recovered with simple distillation. The denser (“heavier”) crude oils produce a greater share of lower-valued products with simple distillation and require additional processing to produce the desired range of products. Heavy crudes are also characterized by a relatively high viscosity and low API gravity (generally lower than 25°) and high percentage of high boiling components (>975° F.).
Additionally, some crude oils also have a higher sulfur content, an undesirable characteristic with respect to both processing and product quality. The quality of the crude oil dictates the level of processing and re-processing necessary to achieve the optimal mix of product output.
In the last two decades, the need to process heavier crude oils has increased. Refined petroleum products generally have higher average hydrogen to carbon ratios on a molecular basis. Therefore, the upgrading of a petroleum refinery hydrocarbon fraction is classified into one of two categories: hydrogen addition and carbon rejection. Hydrogen addition is performed by processes such as hydrotreating and hydrocracking. Carbon rejection processes typically produce a stream of rejected high carbon material which may be a liquid or a solid; e.g., coke.
To facilitate processing, heavy crudes or their fractions are generally subjected to thermal cracking or hydrocracking to convert the higher boiling fractions to lower boiling fractions, followed by hydrotreating to remove heteroatoms such as sulfur, nitrogen, oxygen and metallic impurities.
Further information on hydrotreating catalysts, techniques and operating conditions for residue feeds may be obtained by reference to U.S. Pat. Nos. 5,198,100; 4,810,361; 4,810,363; 4,588,709; 4,776,945 and 5,225,383 which are incorporated herein for this teaching.
Crude petroleums oils with greater amounts of impurities including asphaltenes, metals, organic sulfur and organic nitrogen require more severe processing to remove them. Generally speaking, the more severe the conditions required to treat a given feedstock (e.g. higher temperature and pressures), the greater the cost to build and operate the overall plant.
Worldwide, fixed-bed reactors are utilized considerably more than ebullated-bed reactors. The fixed-bed system is used for lighter, higher quality feedstocks and is a well understood system. Fixed-bed systems are used mostly for naphtha, mid-distillate, atmospheric and vacuum gas-oils, and atmospheric residua treatment.
However, as the feedstock becomes heavier, has a greater level of impurities, or requires more severe conversion levels, the fixed-bed system becomes less effective and less efficient. In these cases, the ebullated-bed reactor systems are better suited for residue processing.
In general, ebullated-bed reactors are utilized to process heavy crude oil feed streams, particularly those feeds with high metals content and high Conradson carbon residue (“CCR”). The ebullated-bed process comprises the passing of concurrently flowing streams of liquids, or slurries of liquids and solids, and gas through a vertically elongated fluidized catalyst bed. The catalyst is fluidized and completely mixed by the upwardly flowing liquid streams. The ebullated-bed process has commercial application in the conversion and upgrading of heavy liquid hydrocarbons and converting coal to synthetic oils.
The ebullated-bed reactor and related process well-known to those skilled in the art and is generally described in U.S. Pat. No. 25,770 to Johanson, which is incorporated herein by reference. Briefly, a mixture of hydrocarbon liquid and hydrogen is passed upwardly through a bed of catalyst particles at a rate such that the particles are forced into random motion as the liquid and gas pass upwardly through the bed. The catalyst bed motion is controlled by a recycle liquid flow so that at steady state, the bulk of the catalyst does not rise above a definable level in the reactor. Vapors, along with the liquid which is being hydrogenated, pass through the upper level of catalyst particles into a substantially catalyst free zone and are removed from the upper portion of the reactor.
Ebullated-bed reactors are generally operated at relatively high temperatures and pressures in order to process these heavy feedstocks. Since such operating parameters substantially increase the cost of designing and constructing the reactors, it would therefore be advantageous to have a system wherein the overall design and manufacturing costs were optimized for specific feedstocks or feedstock components. This optimization would result in a lower initial investment and lower annual operating costs.
Typically, multi-stage ebullated-bed overhead streams processing atmospheric or vacuum residues are combined and sent to additional separation steps including the recovery of light liquids and preparation of a recycle gas which contains any unreacted hydrogen. However, this is not thermally efficient since it requires the streams to be depressurized, cooled down and fractionated, resulting in energy loss.
Alternatively, the combined separator overheads containing significant unreacted hydrogen could be sent to a fixed-bed or ebullated-bed hydrotreater or hydrocracker to hydroprocess the liquids contained in the high pressure vapor plus any external or recycle distillates or VGO. However, even a small amount of entrained vacuum residue and/or fines would render a fixed-bed incapable of processing this feed. Moreover, if the feedrate is high, and if there are high amounts of external streams also requiring hydroprocessing, a single ebullated-bed reactor may not have sufficient capacity to hydroprocess the streams.
It would be therefore desirable to have a configuration which effectively integrates the petroleum atmospheric or vacuum residue hydrocracking and the vacuum gas oil hydrotreating/hydrocracking. Moreover, it would be highly desirable to have a configuration that overcomes the flowrate limitations of conventional designs described above. The present invention overcomes such limitations.
The term “vacuum gas oil” (VGO) as used herein is to be taken as a reference to hydrocarbons or hydrocarbon mixtures which are isolated as distillate streams obtained during the conventional vacuum distillation of a refinery stream, a petroleum stream or a crude oil stream.
The term “naphtha” as used herein is a reference to hydrocarbons or hydrocarbon mixtures having a boiling point or boiling point range substantially corresponding to that of the naphtha (sometimes referred to as the gasoline) fractions obtained during the conventional atmospheric distillation of crude oil feed. In such a distillation, the following fractions are isolated from the crude oil feed: one or more naphtha fractions boiling in the range of from 90 to 430° F. one or more kerosene fractions boiling in the range of from 390 to 570° F. and one or more diesel fractions boiling in the range of from 350 to 700° F. The boiling point ranges of the various product fractions isolated in any particular refinery will vary with such factors as the characteristics of the crude oil source, refinery local markets, product prices, etc. Reference is made to ASTM standards D-975 and D-3699-83 for further details on kerosene and diesel fuel properties.
The term “hydrotreating” as used herein refers to a catalytic process wherein a suitable hydrocarbon-based feed stream is contacted with a hydrogen-containing treat gas in the presence of suitable catalysts for removing heteroatoms, such as sulfur and nitrogen and for some hydrogenation of aromatics.
The term “desulfurization” as used herein refers to a catalytic process wherein a suitable hydrocarbon-based feed stream is contacted with a hydrogen-containing treat gas in the presence of suitable catalysts for removing heteroatoms such as sulfur atoms from the feed stream.
The term “hydrocracking” as used herein refers to a catalytic process wherein a suitable hydrocarbon-based feed stream is contacted with a hydrogen-containing treat gas in the presence of suitable catalysts for reducing the boiling point and the average molecular weight of the feed stream.
SUMMARY OF THE INVENTION
The object of this invention is to provide a new integrated petroleum residue hydrocracking and distillate vacuum gas oil hydrotreating/hydrocracking process configuration.
It is another object of this invention to provide a method for the processing of individual stage overhead vapors from the residue ebullated-bed hydrocracking reactors in separate distillate ebullated-bed reactors to overcome processing limitations at high feedstock throughput rates for conventional designs.
It is a further object of the invention to provide a unique integrated design which utilizes distillate ebullated-bed reactors for diesel and vacuum gas oil processing so as to alleviate issues relating to solids and vacuum residue carryover, which would normally be of concern for fixed-bed reactors.
It is yet a further object of the invention to provide the use of separate distillate ebullated-bed reactors to allow for additional processing capacity for streams other than those from the residue conversion step including straight run, cracked and FCC products.
A novel feature of the invention is the integration of the hydroconversion of heavy atmospheric or vacuum residue product with vacuum gas oil hydrotreating/hydrocracking in an ebullated-bed reactor. In the unique configuration of this invention, the heavy residue from the crude fractionator is sent to a multiple stage atmospheric or vacuum residue conversion process with an interstage separator. The liquid product from the interstage separator between the vacuum residue hydroconversion units is sent to the second-stage vacuum residue ebullated-bed hydroconversion unit for additional processing. The vapor products from the interstage separator and the vapor product from the second stage ebullated-bed hot separator are sent to separate distillate ebullated-bed reactors.
The straight run vacuum gas oil (“VGO”) products (e.g. those typically boiling in the 650-975° F. range) are sent to a feed drum along with additional VGO feeds, which are pumped to pressure and thereafter equally routed to a separate distillate ebullated-bed unit for processing. Although there are many other possible configurations, the one described below has two residue ebullated-bed units operating in series for processing the heavy residue and two distillate ebullated-bed units operating in parallel for the processing of the separator overhead vapors and external feeds consisting of primarily VGO from multiple sources.
More particularly, the present invention describes a process for the integration and treatment of multiple types and sources of hydrocarbons comprising:
A process for the treatment of heavy hydrocarbon feedstream(s) containing vacuum residue comprising:
a) passing said hydrocarbon feedstream into a first residue hydroconversion reaction stage ebullated-bed reactor to provide an effluent, said hydrocarbon feedstream boiling above 650° F. and having 50%-100% wt material boiling above 975° F.; and
b) separating said effluent from the first reaction stage ebullated-bed reactor in an interstage separator, where said effluent is separated into a vapor phase and a liquid phase; and
c) feeding the liquid phase from said interstage separator to a second residue hydroconversion reaction stage ebullated-bed reactor for additional conversion and impurity reduction; and
d) feeding the vapor phase from said interstage separator to a first downstream distillate ebullated-bed reactor for additional hydroconversion and hydrotreatment; and
e) processing the effluent from said second residue hydroconversion reaction stage ebullated-bed reactor to a hot, high-pressure separator to provide a liquid phase and a vapor phase from said high-pressure separator; and
f) feeding said vapor phase from said high-pressure separator to a second downstream distillate ebullated-bed reactor for additional conversion and impurity reduction; and
g) fractionating the liquid phase from said hot, high-pressure separator to produce naphtha, diesel, VGO, and unconverted residue, and
h) recovering effluents from first and second distillate ebullated-bed reactors.
Preferably, the hydrocarbon feedstream contains greater than 60% wt material boiling above 975° F., more preferably greater than 70% or than 80% or than 90%.
In a preferred embodiment, at least one separate source of materials boiling in the vacuum gas oil range (650-975° F.) which could contain materials boiling in the diesel range (350-650° F.) is also fed to at least one downstream distillate ebullated-bed reactor along with the vapor phase from said interstage separator or hot high-pressure separator of step f).
Generally, the effluent from the first downstream distillate ebullated-bed reactor and the effluent from the second downstream distillate ebullated-bed are combined and thereafter sent for hydrotreatment and product separation.
Advantageously, the VGO stream of step g) is thereafter recycled back to the first and/or second distillate ebullated-bed reactors.
In the process according to the invention, the overall conversion percentage of the hydrocarbon feedstream is preferably greater than 50% wt, and more preferably greater than 80%, or than 90% or than 95%.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic flowsheet of the integrated process for the hydroconversion of heavy residue and VGO hydrocracking/hydrotreatment.
DETAILED DESCRIPTION OF THE INVENTION
Crude oil ( 10 ) is first processed through a crude atmospheric fractionator ( 12 ) to create a bottoms stream ( 14 ) boiling above 650° F. and a lighter stream (not shown).
The bottoms stream ( 14 ) from the crude atmospheric fractionator ( 12 ) is thereafter sent to a vacuum fractionator ( 16 ) to create a residue feed stream ( 18 ) boiling above 975° F. and a vacuum gas oil (VGO) stream ( 20 ) boiling between 650° F. and 975° F. The VGO stream ( 20 ) is fed to a VGO feed drum ( 22 ) along with recovered VGO from downstream separation ( 78 ) and VGO from other processes ( 24 ) to create a VGO feed drum stream ( 28 ) and thereafter sent to a first ( 30 ) and second ( 32 ) distillate ebullated-bed reactors as hereinafter described. These additional VGO streams boil in the heavy diesel and vacuum gas oil range (650-1000° F.). Specifically, these streams can include, but are not limited to, external feeds from straight-run atmospheric or vacuum distillate towers, coker derived liquids, solvent deasphalting DAO, and liquid products recycled from the residue conversion unit.
The vacuum residue feed stream ( 18 ) is thereafter combined with a hydrogen stream and sent to a first residue ebullated-bed reactor for hydroconversion.
The effluent from the first residue ebullated-bed reactor ( 42 ) is thereafter sent to an interstage separator ( 44 ) and separated into a vapor phase ( 46 ) and a liquid phase ( 48 ). The interstage separator ( 44 ) is necessitated by the high vacuum residue feedrate as well as the need to minimize the initial investment needed for the plant design.
The vapor phase ( 46 ) will contain naphtha, diesel, some vacuum gas oil, and unreacted hydrogen. The vapor phase ( 44 ) from the interstage separator is combined with a portion of the VGO feed drum stream ( 28 a ) and sent to a first distillate ebullated-bed reactor ( 30 ) for conversion and treatment of the diesel and vacuum gas oils.
The liquid phase ( 48 ) from the interstage separator ( 44 ) is sent to a second residue ebullated-bed unit ( 50 ) for further vacuum residue hydroconversion. The effluent from the second vacuum hydroconversion ebullated-bed reactor ( 54 ) is then sent to a hot, high pressure separator ( 56 ).
The overhead stream ( 60 ) from the hot-high pressure separator ( 56 ) contains product diesel, some VGO, and additional unreacted hydrogen, which are thereafter combined with a portion of the VGO drum feed stream ( 28 b ) and sent to a second distillate ebullated-bed reactor unit ( 32 ) for further hydrogenation of the diesel and hydrogenation and hydrocracking of the vacuum gas oils. It should be noted that additional recycle or make-up hydrogen ( 64 , 65 ) can also be added to the first ( 30 ) and second distillate ebullated-bed reactor ( 32 ).
This second distillate ebullated-bed reactor ( 32 ) is arranged in parallel with the first distillate ebullated-bed reactor ( 30 ) which receives the overhead from the interstage separator ( 46 ) along with a portion of the VGO drum feed stream ( 28 a ). The product streams from the first and second distillate ebullated-bed reactors are thereafter combined and sent for product separation into naphtha, diesel and unconverted VGO.
The bottoms stream ( 70 ) from the hot, high-pressure separator ( 56 ) is thereafter sent to a product separator and fractionator ( 72 ) where it is separated into naphtha, diesel, unconverted residue stream, and a recovered VGO stream ( 78 ). The recovered VGO stream ( 78 ) is thereafter recycled back to the VGO feed drum ( 22 ) for further processing through the first ( 30 ) and second distillate ebullated-bed reactors ( 32 ).
This invention will be further described by the following example, which should not be construed as limiting the scope of the invention.
EXAMPLE 1
Vacuum residue feedstock is processed in a two-stage in series residue ebullated-bed unit. The feedrate to the plant is relatively high (>50,000 BPSD) and near the limit for a single train plant. The vacuum residue conversion system utilized in the example are residue ebullated-bed reactors. In addition to the vacuum residue feed to the residue ebullated-bed reactors, there are other VGO boiling range feedstocks (straight run, coker VGO and FCC cycle oils), which also require hydrotreatment and it is desirable to coprocess these streams in separate distillate ebullated-bed reactors along with the residue ebullated-bed overhead material which contains product diesel and vacuum gas oils. A summary of the feedstocks for this example is shown in Table 1.
This high feedrate and the need to minimize initial investment necessitated the use of interstage separation where a separation vessel between the residue ebullated-bed reactors is used to remove the gas and unreacted hydrogen from the first stage effluent. The liquid from the interstage separator is the feed to the second stage residue ebullated-bed reactor. The mixed-phase reactor product from the second stage effluent is separated in a hot high-pressure separator. The liquid from the hot high-pressure separator is the final heavy liquid product which contains full-range conversion liquids and is sent to downstream separation and fractionation.
In a pre-invention configuration, the two residue ebullated-bed reactor overhead streams would be combined and sent to additional separation steps including recovery of light liquids and preparation of recycle of the unreacted hydrogen. Alternatively, the combined overhead streams could be sent to a fixed-bed or ebullated-bed hydrotreater or hydrocracker to hydroprocess the liquids contained in the high pressure vapor plus any external or recycle distillates or VGO. However, due to the presence of a small amount of entrained vacuum residue and possible inherent or catalyst fines, this material cannot be effectively processed in a fixed-bed reactor system and an ebullated-bed reactor is most appropriate and typically specified. For high capacity situations and where significant quantities of external streams also require hydroprocessing, the flowrate of material to be processed is not possible in a single distillate ebullated-bed reactor. For this example, the C 5 + liquid flowrate to the distillate ebullated-bed system was nearly 68,000 BPSD with inspections summarized in Table 2. This large feedrate cannot be adequately processed in a single distillate ebullated-bed reactor and it is necessary to utilize two reactors. Suitable hydrogenation catalysts for the ebullated-bed reactor include catalysts containing nickel, cobalt, palladium, tungsten, molybdenum and combinations thereof supported on a porous substrate such as silica, alumina, titania, or combinations thereof having a high surface to volume ratio. Typical catalytically active metals utilized are cobalt, molybdenum, nickel and tungsten; however, other metals or compounds could be selected dependent on the application.
The arrangement of the distillate ebullated-bed reactors and apportioning of feedstocks is a key element of the invention. For a typical arrangement, all of the residue feed could be processed in a two reactor stage in series configuration, preferably the whole effluent from the first reactor passing in the second reactor. For this example however and for many applications, this arrangement was found to be infeasible as a result of the large gas volume and limitations on maintaining a liquid continuous reactor system. Combining the two hot high-pressure separator overheads and then equally splitting a high pressure gas stream to a parallel ebullated-bed reactor arrangement is also not technically feasible.
The solution presented in this invention is to have a separate distillate ebullated-bed reactor for each overhead material from the residue ebullated-bed conversion unit. The low-pressure external and recycle liquid feeds are combined in a gasoil drum and with two separate pumps, and fed to the two parallel distillate ebullated-bed reactors, and, in an advantageous mode typically equally fed. Since the interstage and hot high-pressure separator overheads comprise only a small portion of the total liquid reactor feeds, the operating conditions and process performance in each reactor are advantageously nearly identical for attaining the same product quality. An advantage of the invention is to allow lower temperatures in the distillate ebullated bed reactors than in the residue ebullated-bed reactors due to gasoil feed, which result both in better conversion of the gaseous distillates from the residue ebullated-bed reactors and in a less expensive overall process. The overall liquid and gas products are combined and sent to final product separation and fractionation. The combined yields and product qualities from the distillate ebullated-bed unit are shown in Table 3.
The invention may be applied to a wide range of atmospheric/vacuum residue conversion applications including ebullated-bed reactor systems with feed streams including petroleum atmospheric or vacuum residua, coal, lignite, hydrocarbon waste streams, or combinations there of.
TABLE 1
Summary of Distillate Ebullated-Bed and Residue
Ebullated-Bed Feedstocks
SR 1
Coker
Vacuum
Derived
FCC 2
FCC
Feed
Residue
SR VGO
VGO
HCO
HLCO 3
Rate, BPSD
50,120
37,500
6,515
3,200
4,400
Gravity,
3.6
13.5
13.3
5.3
11.9
°API
Sulfur, W %
5.96
3.51
1.7
1.02
0.71
Nitrogen,
0.62
1.63
0.26
0.11
0.04
W %
TBP
Distillation,
V %
C 5 -350° F.
350-650° F.
24.5
81.3
650-975° F.
4.6
100.0
100.0
75.5
18.7
975° F.+
95.4
1 Straight Run
2 FCC HCO = Fluid Catalytic Cracker Heavy Cycle Oil
3 FCC HLCO = Fluid Catalytic Cracker Heavy Light Cycle Oil
TABLE 2
Liquid Feeds to Distillate Ebullated-Bed Unit
Stage 1
Residue
Ebullated
Stage 2
Recycled
VGO Portion
Bed Ovhd
H-Oil
H-Oil
SR
Coker
of FCC
Feed
C 5 ±
Ovhd C 5 ±
VGO
VGO
VGO
HLCO
Total
Rate, BPSD
4,650
4,902
13,499
37,500
6,515
823
67,889
Gravity, °API
43.2
42.7
18.8
13.5
13.3
7.3
18.0
Sulfur, W %
0.25
0.25
0.67
3.51
1.7
1.13
2.35
Nitrogen, W %
0.13
0.13
0.35
1.63
0.26
0.07
0.20
TBP Distillation, V %
C 5 -350° F.
36.9
35.1
4.3
350-650° F.
50.7
52.8
6.3
650-975° F.
12.4
12.1
100.0
100.0
100.0
100.0
89.4
TABLE 3
Net Distillate Ebullated-Bed Reactor Yields and Product Qualities
Yields
W %
V %
Process Performance
H 2 S
2.42
650° F. + CONVERSION,
44.7
W %
NH 3
0.20
Desulfurization, W %
97.2
H 2 O
0.23
Nitrogen Removal, W %
79.3
C 1
0.68
Hydrogen Cons., SCF/BBL
1,110
C 2
0.64
Capacity, BPSD (C 5 + )
67,900
C 3
0.84
Number of Reactors
2
C 4
0.68
1.10
Feed Gravity, °API
18.0
C 5 -350° F.
14.68
19.18
Feed Sulfur, W %
2.35
350-650° F.
31.95
35.21
Feed Nitrogen, W %
0.20
650-975° F.
49.46
51.56
Total
101.78
107.05
Product
Gravity
Qualities
°API
S, WPPM
N, WPPM
C 5 -350° F.
63.9
200
70
350-650° F.
33.2
330
120
650-975° F.
24.3
1,100
760
The invention described herein has been disclosed in terms of specific embodiments and applications. However, these details are not meant to be limiting and other embodiments, in light of this teaching, would be obvious to persons skilled in the art. Accordingly, it is to be understood that the drawings and descriptions are illustrative of the principles of the invention, and should not be construed to limit the scope thereof.
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This invention relates to a novel integrated hydroconversion process for converting heavy atmospheric or vacuum residue feeds and also converting and reducing impurities in the vacuum gas oil liquid product. This is accomplished by utilizing two residue hydroconversion reaction stages, two vapor-liquid separators, and at least two additional distillate ebullated-bed hydrocracking/hydrotreating reaction stages to provide a high conversion rate of the residue feedstocks.
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BACKGROUND
[0001] This invention relates to a sleeping cot, lightweight enough to be used by backpackers and mountaineers in lieu of the more commonly used therma-rest (inflatable pad) or the ridge rest (foam pad).
SPECIFICATION
[0002] 1. Discussion of Prior Art
[0003] Currently in the sports of backpacking and mountaineering, the only lightweight sleeping pads are the therma-rest and the ridge rest. These sleeping pads, although relatively comfortable, have some significant disadvantages. For example: a therma-rest, while providing comfort and insulation, can fail if the barrier is breached causing an air leak and leaving the user in the position of sleeping on cold, icy, rocky, uncomfortable ground. The ridge rest being the lighter of the two is less comfortable and provides less insulation.
[0004] Prior art has discussed the use of a backpack cot, i.e. U.S. Pat. No. 5,590,825, where the cot is incorporated into the external frame backpack. The disadvantages of this idea are that you are basically doubling the weight of your backpack. In addition, you are removing the storage capability of your pack for camping. You would have to displace the entire contents of your pack in order to deploy your cot. Furthermore, the external frame required for this patent has greatly decreased in popularity over the last two decades for many reasons and current users of the external frame pack are not the target markets of this invention.
[0005] 2. Objects and Advantages
[0006] The Backpacker/mountaineers cot will provide a lightweight, comfortable and firm flat sleeping surface regardless of the ground conditions. The cot incorporates tools already in use by the backpacker/mountaineer and therefore will have little effect on increasing the weight to be carried. Currently, many avid backpackers and mountaineers employ the use of telescoping ski poles or trekking poles, an ice ax if the terrain demands it and an internal frame pack. By incorporating all option levels of the Hicks cot, you would be carrying the cot cloth and six 6 inch legs. The trekking poles become the end stays of your cot. The ice ax is your center stay and the side rails come from the main stays of your internal frame pack. In addition, several different brands of internal frame packs use a relatively similar main stay system, a conversion from existing mainstay design to a mainstay that can act as the siderails of the cot can be manufactured to retrofit an individual current pack allowing the owner to keep his/her original pack. The conversion will match up the metal stay ends of the existing pack requirements with telescoping siderails of the cot. The retrofit will then be made with varying sizes. The adjustable side rails and conversion could thus replace the existing mainstays. This full use of existing tools is called option 1.
[0007] When option 1 is not what the owner is interested in because he/she is happy with their current pack or the owner cannot afford the new pack, an individual can use option 2. Option 2 requires the user to carry the side rails in addition to the cloth and the six 6 inch legs. The increase in weight would be relative to a backpacker adding a sleeping pad chair to his/her pack. Special note: the sleeping pad chair is a popular option for backpackers that uses four independent poles stretched over by nylon with pockets on each end to stuff the foam sleeping pad or inflatable sleeping pad. Then the user uses straps to cinch the chair into a sitting position. Option 2 would only require the use of the ski poles and the ice ax. I will also note at this time that the backpacker/mountaineers cot will incorporate the use of four independent side rails and adjustable side straps so the user can use the cot as a camp chair similar to the sleeping pad chair. The ice ax connections to the cot center legs will require a receiver for the point of the ice ax and then a receiver for the shaft of the ice ax on the other end in order to accommodate different size ice axes. The end receiver legs will be constructed as a trekking pole point receiver leg and trekking pole handle receiver leg.
[0008] Option 3 is simply the backpacker option. When using option 3, the only dual use incorporated is the use of the ski poles as the end stays. A standard center stay is used in lieu of the ice ax. Of course, the user could also elect to use the option four backpack, without the ice ax and still be lightweight. The center stay will be the ice ax extender used to extend the length of shorter ice axes in order for the ice ax to fit to the cot as a center stay. The ice ax extender will come in a length that is fitted to the size of the center cot main stay but can be cut down by the user if he/she decides to use the ice ax center stay option.
[0009] Option 4 is simply an ultra light cot. It is not as light as a sleeping pad, but a perfect option for the packer looking for comfort. Option 4 could have a secondary target market in the hunter who is looking for the ultra light comfort, but with no need for the other options.
[0010] In addition, various cot cloths should be included in the options: a lighter weight mesh for warmer environments, an insulated cot for cold weather and a standard nylon single layer cloth for normal conditions.
DESCRIPTION
[0011] The following descriptions refer to drawing pages 1 through 5 . Each page has two drawings referenced as A and B. A and B refer to different angles of the same subject matter. Existing products are not detailed here, only the detail of the invention as it relates to those existing products.
[0012] Drawing page 1 is an overall look at the cot when it is assembled and the position of all of the related material necessary to have the-cot assembled. FIG. 1 a is an above view of the cot. The cot fabric is standard cut length and width of existing cots with sleeves down the length of the cot to hold the side rails. There are four side rails for the cot, each approximately ½ the length of the cot. The side rails will be made to telescope in order to facilitate easier packing or adjust to the use as a main stay of internal frame packs. At each end of each side rail is a lock button and lock similar to that used on umbrellas. This lock secures the side rail to each of the six legs of the cot. At each end of the cot are the trekking poles. These trekking poles are on the market today and have a telescoping feature that would allow them to be used as the end stays of the cot. By reducing the trekking pole to the proper length, inserting them into the end legs and then tensioning the trekking pole, the proper fit could be found. The center stay is made from the ice ax. If the ice ax is not used as a center stay, the ice ax extender will be used as the center stay. The ice ax extender will come in a standard length so it functions as a center stay. The user can then cut down the extender to the proper length if they chose to use the ice ax as a center stay. The position of the ice ax on the leg will be lower down so as not to interrupt the sleeping surface of the cot as shown in FIG. 1 b. In addition, an incline strap will be sewn into the cot in order for the user to raise the cot into a camp chair position for uses other than sleep. The center leg will have a swivel screw in order for this to occur. The detail of the legs that receive the ice ax, trekking poles and side rails are detailed in drawing pages 2 through 5 .
[0013] Drawing page 2 refers to the end legs that receive the trekking pole tip. There is a side view, 2 b, that shows approximate location of the pole tip receiver hole on the end legs. There will be two pole tip receiver legs. One for each trekking pole. 2 a shows how the side rail is received by the leg and how the side rail lock is situated. Also noted in 2 a is the rubber boot added to the end of each leg in order to reduce damage to the cot leg and the tent floor of the user. This rubber boot will also reduce slippage on slippery surfaces. FIG. 2 b is the same leg as 2 a only rotated 90 degrees to show how the trekking pole tip is received into the receiving leg. The tapered design of the pole will stop the advance of the pole through the leg beyond the tip. There is no locking mechanism for the tip of the pole because the pole will be tensioned after insertion into the legs by its existing telescoping feature. Drawing page 3 refers to the receiver legs that receive the other end of the trekking pole or the “trekking pole handle” receiver leg. Again as in drawing 2 a, the side rail receiver hole is shown as is the side rail and associated locking mechanism. FIG. 3 a shows how the pole handle receiver cup is in position to the rest of the leg components. In FIG. 3 b which is the same as 3 a except turned 90 degrees. The pole handle receiver cup shows the required concavity of the handle receiver leg. This is required so as the user tensions the trekking pole and uses the cot, the pole will not slip out of position. Again, there is not a locking mechanism for the trekking pole because the tension of the telescoping pole and the receiver hole design of each leg will lock the pole in place.
[0014] Drawing pages 4 and 5 refer to the center legs of the cot. There will be one of each type of center leg. One leg that receives the point of the ice ax and one leg that receive the shaft of the ice ax. Drawing page 4 refers to the center leg that receives the point of the ice ax. In FIG. 4 a, the location of the ice ax receiver hole is below the side rail receiver hole. This is needed because the ice ax if positioned above the side rail, would interfere with the sleeping surface of the cot. In addition, the upper portion of the center leg is reserved for the swivel motion of the cot incline feature. The FIG. 4 a shows the dotted lines to suggest the various positions of the side rail as it is adjusted with the incline strap. The center of the side rail receiver hole will have a swivel screw that is free floating in the up and down motion. The siderail lock button and lock are again shown. FIG. 4 b is the same as 4 a except turned 90 degrees to show how the ice ax point is received in relation to the other components of the leg. The nature of an ice ax point, which tapers out to the ice ax shaft, will allow this leg to not require a locking mechanism.
[0015] Drawing page 5 details the other center leg which receives the shaft and head position of the ice ax as noted again in 5 a, the side rail receiver swivel screw and various possible incline positions. The shaft receiver hole shows the required size of the hole and the locking screw, which would clamp down onto the ice ax shaft after it has been properly tensioned onto the cot. FIG. 5 b is the same as 5 a except turned 90 degrees to show the receptor and relating position of the ice ax to the center leg.
[0016] Special note: Refer to drawing page 6 . Ice axes come in various lengths depending on its intended use and the height of its user. Therefore, it may be required to make an “ice ax point extender”. This extender would fit onto the point end of the ice ax, extending its length. There will be a securing screw to hold the extender in place on the ice ax. The extender will come in a standard length which after being sized by its owner, will be cut down in order to save weight. This extender will come in a standard length that will serve as the center stay of the cot if the ice ax is not going to be used as a center stay by the user.
OPERATIONS
[0017] Needed for operations are the following:
[0018] 1. Six ft. by 2½ ft. nylon cot fabric with incline strap.
[0019] 2. Two pole point receiver legs
[0020] 3. Two pole handle receiver legs.
[0021] 4. One ice ax point receiver leg.
[0022] 5. One ice ax shaft receiver leg.
[0023] 6. Four telescoping siderails. (Adapted from internal frame backpack stays).
[0024] 7. Ice ax
[0025] 8. Ice ax extender. (center stay)
[0026] 9. Two telescoping trekking poles.
[0027] The user will lay the cot fabric on the ground insert extended siderails in sleeves. Insert siderails into all six legs and lock into place. Insert point of treking pole into leg and size so handle fits into appropriate leg. Extend pole until tensioned and tighten down telescoping screws of pole. Repeat for other end of cot. Insert ice ax shaft through ice ax shaft receiver leg hole. Inset point of ice ax into ice ax point leg hole. If needed the ice ax extender can be added at this point. Tension ice ax so cot becomes tight. Tighten ice leg screw on ice ax shaft. Cot is ready for use.
SUMMARY
[0028] The backpackers/mountaineers cot will be a great addition to anyone's backcountry experience. With the relative little difference in weight to be carried, the backpacker could greatly increase his/her comfort regardless of ground conditions. By using tools already being used for other purposes the user is reducing overall weight while greatly increasing comfort. The parallels of equipment is as follows: The user has trekking poles, ice ax, sleeping pad, sleeping pad camp chair and internal frame backpack. The cot user will exchange the sleeping pad and chair for the cot fabric and six cot legs. By adapting the internal frame backpacking stays into the siderails of the cot and using the trekking poles and ice ax as the end and center stays of the cot the user will have the ultimate in efficiency and comfort in the backcountry environment.
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A backpacker/mountaineers cot lightweight enough to be carried in the backcountry using tools already employed for other purposes and carried by the user. The user is exchanging the use of foam or inflating sleeping pad and sleeping pad camp chair for a cot fabric and six cot legs. The user then incorporates the trekking poles, ice ax and internal frame backpack stays for the appropriate assembly of the cot.
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PRIORITY CLAIM
In accordance with 37 C.F.R. 1.76, a claim of priority is included in an Application Data Sheet filed concurrently herewith. This application is a continuation of U.S. application Ser. No. 14/922,590, entitled “INTERVERTEBRAL EXPANDABLE SPACER,” filed Oct. 26, 2015, now U.S. Pat. No. 9,642,722, which is a continuation-in-part of U.S. patent application Ser. No. 14/021,482, entitled “INTERVERTEBRAL SPACER,” filed Sep. 9, 2013, now abandoned, which is a divisional of U.S. patent application Ser. No. 12/496,824, entitled “INTERVERTEBRAL SPACER,” filed Jul. 2, 2009, now U.S. Pat. No. 8,529,627, issued Sep. 10, 2013. The contents of the above referenced applications are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
The invention relates to spinal implants for intervertebral body fusion devices and an instrument for properly inserting the implant between the vertebral bodies.
BACKGROUND OF THE INVENTION
The spine is a complex structure capable of performing a broad range of kinematic functions. The spinal vertebrae and elastic disk permit the spine to move in three axes of motion. These axes include rotation, such as twisting of the upper back and shoulders relative to the pelvis, horizontal movement, such as forward (anterior) or backward (posterior), and lateral bending movement to either the right or left side.
The spacing between adjacent vertebrae is maintained by a disc having both elastic and compressible characteristics. The appropriate spacing in a healthy spine is maintained between adjacent vertebrae during the rotational, horizontal and lateral movement of the spine, thereby allowing for maximum freedom of motion of the spine. The spacing between adjacent vertebrae is also critical to allow the nerves radiating from the spine to extend outwards without being pinched or compressed by the surrounding vertebrae.
Spinal discs can be damaged by physical injury, disease, genetic disposition, and aging, and become less than fully functional. When this happens, the disc is incapable of maintaining the proper intervertebral spacing and, as a result the nerves radiating from the spine can be compressed. Nerve damage could also be caused by root compression in neural foramen, compression of the passing nerve, and an enervated annulus which occurs when the nerves flow into a cracked annulus that results in pain each time the disc is compressed. Obviously other organic abnormalities can occur in the presence of a dysfunctional disc.
Many solutions have been developed to eliminate or at least minimize nerve compression and the attendant pain that commonly results from spinal nerve pressure. These solutions approach the problem by surgically removing the defective disc and thereafter replacing it with an insert that is subsequently fused to the adjacent discs, thereby maintaining an appropriate distance between adjacent vertebrae. While prior insert solutions have been successful in improving the patient's condition, it is somewhat problematic for the surgeon to gain the necessary access to the space between the vertebrae without doing harm to adjacent body structures such as the spinal cord, other nerves, and other adjacent body organs.
A surgical solution that utilizes a less invasive technique will result in less trauma and unintended damage to surrounding bone, organ, muscle and nerve tissue while achieving the desired results. The present invention relates to an insert that can be advanced into a prepared space between vertebral bodies by a novel instrument, and, upon reaching the appropriate insertion point, a pivotal motion is imparted to the insert to provide proper placement of the insert. The pivotable insert provides the surgeon with the capability to implant the insert using a nonlinear path. The insertion and placement is achieved in a minimally invasive manner.
DESCRIPTION OF THE PRIOR ART
What is needed, therefore, is an intervertebral insert and delivery instrument that will be minimally invasive.
U.S. Published Patent Application No. 2008/0009880 discloses a pivotable interbody spacer system includes an insertion instrument configured to manipulate a pivotable interbody spacer during surgical insertion; wherein the insertion instrument includes means for coupling the interbody spacer and a means for fixing the angular position of the interbody spacer. According to one exemplary method for inserting the interbody spacer in a spinal disc space, the interbody spacer is grasped by the insertion instrument and fixed at a first angular position; the interbody spacer is inserted into the surgical site; the interbody spacer is released from the first angular position; the insertion instrument is pivoted about the coupling such that the interbody spacer is in a second angular position; the angular position of the interbody spacer is fixed in the second angular position; and the insertion process continues until the interbody spacer is positioned in the desired location.
U.S. Published Patent Application No. 2008/0221694 discloses a spinal spacer system which includes a handle member and an extension member including a first and a second end, wherein the first end of the extension member is coupled to the handle member. Additionally, a coupling device configured to selectively couple a spacer to the second end of the extension member is disposed on the extension member and includes an angular fixation member configured to fix the spacer in an angular position relative to the handle member. The spinal spacer system also includes an actuator configured to selectively actuate the coupling device and the angular fixation member.
U.S. Published Patent Application No. 2008/0140085 discloses a method to insert a spinal implant into a vertebral space, the method including the steps of: grasping the implant with a distal end of an implant insertion tool; holding a proximal end of the implant insertion tool and inserting the implant toward the vertebral space; and manipulating the proximal end to apply a yaw movement to the implant while the implant is attached to the tool and in the vertebral space. Two slideable rods inside sheath 1514 activate rotation of the spacer implant.
U.S. Published Patent Application No. 2008/0109005 discloses a system for replacing a natural nuclear disc in an intervertebral space which has a spinal device configured for placement in the intervertebral space. An insertion tool is configured for holding the spinal device while the spinal device is inserted into the intervertebral space. A gripping member of the insertion tool has an end for adjustably holding the spinal device within the intervertebral space. A steering actuator of the insertion tool is operatively connected to the spinal device and configured for pivoting the adjustably held spinal device within the intervertebral space while the steering actuator is controlled remotely from the intervertebral space.
U.S. Published Patent Application No. 2003/0208203 discloses instruments and methods for inserting one or more implants to a surgical site in a patient in a surgical procedure, including minimally invasive surgical procedures. The implant is mountable to the instrument in a reduced profile orientation and after insertion is manipulated with the insertion instrument to the desired orientation.
U.S. Published Patent Application No. 2008/0065082 discloses instruments and methods for inserting a rasp into an intervertebral space of a spine and using the rasp to decorticate the adjacent vertebra. More particularly, one embodiment provides an instrument that actively changes the angle of the rasp relative to the instrument. The delivery instrument may use a gear portion to articulate the rasp. A second gear on the rasp may mate with a corresponding gear on the instrument. As the instrument gear rotates relative to the instrument, the instrument gear drives the rasp gear, thereby rotating the rasp to decorticate the vertebra. Trial inserts and methods are also provided to determine an appropriate size of a rasp for decortications.
U.S. Published Patent Application No. 2007/0225726 discloses a method, apparatus, and system provided to place an insert in a space between boney structures. The insert may be rotatably coupled to the delivery instrument. The delivery instrument may comprise a body and an articulating member. The articulating member may slidably interact with the insert to rotate the insert about a pivot point. A first actuator is operatively coupled to the articulating member, such that actuating the first actuator translates the articulating member relative to the body. An engagement member may be coupled to the body and adapted to releasably and rotatably secure the insert to the delivery instrument. The articulating member and the engagement member may be offset from each other in such a manner that when the articulating member engages the insert, the insert rotates relative to the delivery instrument. Alternatively, the insert may be coupled to the delivery instrument via rotatable attachment members.
U.S. Published Patent Application No. 2005/0192671 discloses an artificial disc device for replacing a damaged nucleus. In one form, the device may be inserted in components such that the device may be assembled within and retained by the natural annulus therein. In another form, the device may be inserted into the natural annulus in a collapsed or compressed state or arrangement and then be expanded within and retained by the annulus therein. In a further form, the device may be provided with a releasable connection so that the device may be connected in an insertion configuration, and may be released in an operable configuration.
U.S. Pat. No. 7,976,549 discloses a method and apparatus to place an insert in a space between boney structures. An articulating member slidably interacts with the insert to rotate the insert about a pivot point.
U.S. Pat. No. 8,043,293 discloses a pivotable implant having an inner cavity and a plurality of teeth formed on one end of the implant. An insertion instrument includes a retractable latching mechanism and an internal gear configured to mate with the teeth formed on the implant.
What is lacking in the art is a pivotable expandable implant and associated surgical implant tool.
SUMMARY OF THE INVENTION
The instant invention is comprised of a pivotable expandable insert that is positioned in a prepared space between adjacent vertebrae. The insert has an approximately centrally located pivot post and a curved end portion, each configured to cooperatively engage an instrument to advance the insert into an appropriate position. Various components of the instrument are manipulated to achieve the final placement of the insert. The instrument is then disengaged from the insert and removed from the patient. An adjustment screw is then used to engage the expandable insert to splay opposing side surfaces to a distance as required by the installation.
Accordingly, it is an objective of the instant invention to provide a spinal insert that is easily and accurately placed within a prepared space between two vertebrae using a minimally invasive technique.
Still another objective of the invention is to provide an implant that is compact in size for installation and expandable upon insertion, minimizing the stress placed on the body during installation.
It is a further objective of the instant invention to provide a surgical instrument configured to be operatively connected to the implantable insert that can be used by the surgeon to accurately place the insert within the intervertebral space using a minimally invasive technique, and expand the insert upon placement.
It is yet another objective of the instant invention to provide simple and reliable mechanical relationships between the insert and the surgical instrument to provide a minimally invasive approach to implanting a spinal insert.
It is a still further objective of the invention to provide an insert that will stabilize the spine and promote bone growth between adjacent vertebrae such that adjacent vertebrae are fused together.
Yet still another objective of the invention is to provide an insert that reduces the need for maintaining an inventory of different sized implants by providing an implant that is adjustable in size.
Other objectives and advantages of this invention will become apparent from the following description taken in conjunction with any accompanying drawings wherein are set forth, by way of illustration and example, certain embodiments of this invention. Any drawings contained herein constitute a part of this specification and include exemplary embodiments of the present invention and illustrate various objects and features thereof.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a top view of the implantable insert.
FIG. 2 is a side view of the implantable insert.
FIG. 3 is a bottom view the implantable insert.
FIG. 4 is a side view of the implantable insert opposite to that shown in FIG. 2 .
FIG. 5 is a perspective view of the surgical instrument utilized to implant the insert.
FIG. 6 is a side view of the surgical instrument and implantable insert.
FIG. 7 is a top view of the surgical instrument and implantable insert.
FIG. 8 is a side view of the surgical instrument and implantable insert opposite to that shown in FIG. 6 .
FIGS. 9A, 9B, 9C, 9D, and 9E show the placement of the insert and the operative relationship of the surgical instrument at various stages of the insertion procedure.
FIG. 9F shows an alternative embodiment that utilizes a threaded implant interface.
FIG. 10 is a top view of an expandable implantable insert.
FIG. 11 is a side view of the expandable implantable insert.
FIG. 12 is a perspective view of the expandable implantable insert.
FIG. 13 is a top view of the expandable implantable insert in an expanded configuration.
FIG. 14 is a side view of the expandable implantable insert in an expanded configuration.
FIG. 15 is a perspective view of the expandable implantable insert in an expanded configuration.
FIG. 16 is an exploded view of the expandable implantable insert.
FIG. 17 is a frontal exploded view of the expandable implantable insert without the frame.
FIG. 18 is a rearward exploded view of FIG. 17 .
FIG. 19 is a cross sectional view of the expandable implantable insert.
FIG. 20 is a cross sectional view of the expandable implantable insert in an expanded configuration.
FIG. 21 is a side view of the expandable implantable insert mounted to a surgical implant tool.
FIG. 22 is a side view of the expandable implantable insert mounted to a surgical implant tool in a rotated position.
DETAILED DESCRIPTION OF THE INVENTION
Referring to FIGS. 1-9 in general, FIG. 1 is a top view of implantable insert 1 . Insert 1 is generally arcuate in shape and has a top surface 2 and a bottom surface 4 . Connecting top surface 2 and bottom surface 4 is a convex edge 6 on one side and a pair of concave edges 8 A and 8 B on the second, opposite side. The edges have first end portions 10 A and 10 B and second end portions 12 A and 12 B. A first curved portion 14 connects first end portions 10 A and 10 B and a second curved portion 16 connects second end portions 12 A and 12 B. Located on the top surface 2 is a plurality of apertures 18 A. Likewise, bottom surface 4 has a plurality of apertures 18 B. Apertures 18 A and 18 B form a substantially hollow center within the insert 1 . The hollow cavity within the insert is used to deliver a bone growth material to fuse the adjacent vertebrae together. The insert 1 is relatively small in overall size while providing both a large surface for support and a large cavity to provide bone growth material. A slotted passageway 20 is formed on the second side surfaces including the entire length of concave surface 8 B and a portion of concave surface 8 A. The slot 20 is also continued through first curved portion 14 . Insert 1 also includes a first cylindrical post 22 extending between, and attached to, the top surface 2 and bottom surface 4 at a first end portion of the insert 1 . Likewise, a second cylindrical post 24 extends between, and is attached to, the top surface 2 and bottom surface 4 at a second end portion of the insert 1 . A third cylindrical post 26 is located approximately midway between the first and second post in a location adjacent to the area where concave surfaces 8 A and 8 B approach one another.
FIG. 2 is a side view of insert 1 showing the pair of concave surfaces 8 A and 8 B, first curved portion 14 and second curved portion 16 . Also shown in FIG. 2 is slotted passageway 20 which extends from concave surface 8 A, through concave surface 8 B and continues into first curved portion 14 . Also illustrated in FIG. 2 is a first post 22 and third post 26 .
FIG. 3 is a bottom view of insert 1 showing bottom surface 4 , convex surface 6 on the first side and the pair of concave edges 8 A and 8 B on the second side, as well as first curved portion 14 and second curved portion 16 . Also illustrated in FIG. 3 are apertures 18 B.
FIG. 4 is a side view of insert 1 that showing the alternative side to that shown in FIG. 2 showing the convex surface 6 on the first side as well top surface 2 , bottom surface 4 , first curved portion 14 and second curved portion 16 . Also shown in FIG. 4 is a portion of slotted passageway 20 . As can best be seen in FIG. 4 the top surface 2 and bottom surface 4 are generally domed shaped with the high points 4 A and 2 A of each dome being located in the area surrounding the areas where the third cylindrical post 26 connects to the top and bottom surfaces respectively. These high points will form contact points with adjacent vertebrae, thereby facilitating pivotal motion of the insert about the third post 26 .
FIG. 5 is a perspective view of insert 1 mounted on surgical instrument 30 prior to implantation. The instrument 30 includes a sleeve 32 and an arm 34 . The arm 34 is mounted for relative reciprocal longitudinal movement with respect to sleeve 32 . The sleeve 32 includes a guide rail 36 . The guide rail 36 presents two tracks formed, with one formed on each side of a slot 38 designed to receive arm 34 . The arm 34 includes profiled surfaces formed on opposite sides of the arm 34 that are configured to operatively engage the tracks formed on the guide rail 36 . The sleeve 32 also includes a pair of curved surfaces 42 formed on opposite side of sleeve 32 that are shaped to mate with the first curved portion 14 of insert 1 .
FIG. 6 is a side view of insert 1 attached to surgical instrument 30 . In this view, concave surfaces 8 A and 8 B of the first side are shown. Also shown in this view is sleeve 32 , arm 34 , guide rail 36 and a gripping mechanism 40 .
FIG. 7 is a top view of the insert 1 attached to the surgical instrument 30 . In this view top surface 2 of the insert 1 is shown. As shown in this figure, surgical instrument 30 includes the sleeve 32 with mating surface 42 , arm 34 and gripping mechanism 40 .
FIG. 8 is a side view of insert 1 and surgical instrument 30 showing the side opposite to that shown in FIG. 6 . Convex surface 6 on insert 1 can be seen in this view. Also shown in this view is the sleeve 32 and gripping device 40 of surgical instrument 30 .
FIGS. 9A through 9E show the placement of the insert within the prepared space between the vertebrae, and the operative relationship of the surgical instrument and the insert at various stages of the procedure. As shown in FIG. 9E , arm 34 has a recess 46 that includes an aperture that is cylindrical in cross section. The recess can receive the third post 26 and is capable of retaining or releasing the post dependent upon on direction of the forces applied thereto. As shown in FIG. 9A , post 26 on insert 1 has been position within recess 46 on arm 34 . Likewise, the first end portion 10 on insert 1 is positioned to be in mating relationship with curved mating surfaces 42 located on sleeve 32 . The insert 1 as shown in FIG. 9A , is then inserted into the prepared site between adjacent vertebrae. Thereafter, instrument 30 is manipulated by gripping device 40 to advance the insert 1 toward a point that would be appropriate for rotation of the insert 1 . Upon reaching the pivot point, the sleeve 32 is retracted as shown in FIG. 9B and the instrument 30 is moved medially to impart the initial rotation. At this point, the instrument 30 is tamped slightly to impart a small amount of rotation to the insert 1 . Having been positioned as shown in FIG. 9C the sleeve 32 is advanced such that a corner portion 44 on the sleeve 32 makes contact with the first end portion of the insert 1 . The further advancement of sleeve 32 will result in the rotation of insert 1 about the post 26 which is retained in position by arm 34 . Additional tamping of the instrument 30 may be necessary. The sleeve 32 is advanced until the insert is rotated into its final position as shown in FIG. 9D . At this point, the sleeve 32 is retracted and the mating surfaces 42 are withdrawn from engagement with the first end portion 10 . As shown in FIG. 9E the instrument 30 is then manipulated such that the post 26 is removed from recess 46 and the instrument 30 is then released from the insert 1 . At this point the instrument 30 is removed from the prepared site. Bone growth material is provided in the hollow cavity formed within the insert 1 . Apertures 18 A and 18 b permit bone in growth with the insert 1 and adjacent vertebrae. As an alternative to the recess shown in FIG. 9E the arm 34 is provided with a threaded implant interface in the form of an externally threaded pin 48 that will threadably engage and disengage from a threaded bore that extends transversally to the longitudinal axis of the post 26 , as shown in FIG. 9F .
Referring in general to FIGS. 10-22 , the expandable implant 100 is generally arcuate in shape having a top surface 102 and a bottom surface 104 . A frame 106 has a convex edge 107 on one side and a convex edge 108 on the opposite side forming an inner side wall 111 . The edges have first end portions 112 and second end portions 114 . A first curved portion 110 connects first convex edge 107 to the second convex edge 108 on one end, and a second curved portion 116 connects said second convex edge 108 to said first convex edge 107 on the opposite end. A first insert 120 is constructed and arranged to fit within the inner side wall 111 of said frame 106 . The first insert 120 is defined by the top surface 102 having a first edge sleeve 122 cooperates with first frame alignment post 124 . A second edge sleeve 126 cooperates with a second frame alignment post 128 . A third edge sleeve 130 cooperates with a third frame alignment post 132 . A fourth edge sleeve 138 cooperates with a fourth alignment post 140 . Aperture 142 accepts an upper end 144 of adjustment post 150 . The upper end 144 is sized to allow rotation of the adjustment post 150 used during installation and displacement of the first insert 120 . The adjustment post 150 includes a threaded aperture 152 for receipt of a surgical insert tool 300 for installation. The threaded aperture 152 further receives an adjustment screw 154 which is used for displacement of the inserts. The frame 106 includes a slotted passageway 133 for ease of access to the adjustment screw 150 , and for placement of bone growth material.
A second insert 170 is constructed and arranged to fit within the inner side wall 111 of said frame 106 . The second insert 170 is defined by the bottom surface 104 having a first edge sleeve 172 that cooperates with first frame alignment post 124 . A second edge sleeve 174 cooperates with a second frame alignment post 128 . A third edge sleeve 176 cooperates with a third frame alignment post 132 . A fourth edge sleeve 178 cooperates with a fourth alignment post 140 . Aperture 180 accepts a lower end 182 of adjustment post 150 . The lower end 182 is sized to allow rotation of the adjustment post 150 used during installation and displacement of the lower insert 170 . Additionally, post 141 of first insert 120 can be used to engage a reciprocal post 143 of the lower insert 170 .
A wedge member 200 is positioned between the first insert 120 and the second insert 170 . The wedge member 200 includes a lower ramp surface 202 which cooperates with a lower angled surface 204 on the lower insert 170 . Similarly, an upper ramp surface 206 cooperates with an upper angled surface 208 on the upper insert 120 . As illustrated in FIGS. 19 and 20 , the rotation of screw 154 within the adjustment post 150 pushes the wedge member 200 away from the post, wherein the lower ramp surface 202 slides up the lower angled surface 204 , as does the upper ramp surface 206 which slides up the upper angled surface 208 . The ramps share a common proximal end with angled ramp surfaces that separated distal ends that position the upper and lower inserts in an expanded configuration. Movement of the wedge member 200 causes displacement of the upper surface 102 and lower surface 104 at equal rates. The wedge member 200 further includes lower guide posts 220 and 222 which engage lower slots 224 and 226 on the lower insert 170 . Similarly, upper guide posts 228 and 230 engage upper slots, not shown, forming a mirror image of the lower slots 224 , 226 .
Frame 106 further includes a pivot post 240 mounted along end 112 , wherein frame 106 has a first and second tang 117 and 119 extending between the edges 106 and 108 . A mounting aperture 121 is placed within the first tang 117 and mounting aperture 123 is placed within the second tang 119 .
For placement of the implant 100 between the vertebra, the receive arm 34 is threaded as shown in FIG. 9F and used to engage the adjustment post 150 . The pivot post 240 is engaged and, as illustrated in FIGS. 9A-9D , the implant rotated from a storage position as depicted in FIG. 21 , to a mounting position as depicted in FIG. 22 . The operative relationship of the surgical instrument 300 allows the threading of the adjustment post 150 by rotation of the knob 302 . Thereafter, the instrument 300 is manipulated by gripping device 304 to advance the implant toward a point that would be appropriate for rotation. Upon reaching a pivot point, the instrument 300 is moved medially to impart an initial rotation. At this point the instrument 300 can be tamped slightly on the knob 302 to impart a small amount of rotation to the implant. The grip 304 is drawn to the handle 306 to cause rotation, and once the implant is in position, the tool is removed from the insert by unthreading rotating of the knob 302 until the threaded end is released from the implant. The surfaces 102 and 104 can then be expanded by the use of the screw 154 to engage the adjustment post 150 . The screw is rotated to engage the wedge member 200 , wherein the wedge member is used to expand the surface 102 and 104 . With the surfaces expanded, bone growth material can be placed into the hollow cavity formed within the implant.
All patents and publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
It is to be understood that while a certain form of the invention is illustrated, it is not to be limited to the specific form or arrangement herein described and shown. It will be apparent to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is shown and described in the specification and any drawings/figures included herein.
One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objectives and obtain the ends and advantages mentioned, as well as those inherent therein. The embodiments, methods, procedures and techniques described herein are presently representative of the preferred embodiments, are intended to be exemplary and are not intended as limitations on the scope. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention and are defined by the scope of the appended claims. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the art are intended to be within the scope of the following claims.
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An intervertebral insert member and an instrument for positioning the insert in a space between vertebral bodies in vivo. The insert member is advanced by the instrument into a prepared site located between adjacent vertebral bodies. Upon reaching the appropriate insertion point, the sleeve is retracted and a pivotal motion is imparted to the insert. The insert member is pivotally attached to the distal end of the delivery instrument such that it can be articulated about a pivot point that is located on the insert member until it is properly positioned. The positioning instrument is then released from the insert member and removed from the space between the vertebral bodies. An adjustment screw is available to expand the surfaces of the insert member by displacement of a wedge member within the insert.
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BACKGROUND OF THE INVENTION
[0001] Two-wheeled vehicles, such as bicycles or motorcycles, tend to be unstable when they are not in motion. Without some additional support means, such as a kick stand, gravity causes a stationary two-wheeled vehicle to fall over. People who own, transport or service a two-wheeled vehicle often have a need to maintain the vehicle in a substantially vertical position. While a kickstand generally suffices to support the vehicle at rest, the use of a kickstand alone is often inadequate where the vehicle is subject to other forces, such as on uneven or slopping ground. A stationary two-wheeled vehicle on solid ground may even be subjected to external forces by gusting winds or flowing water, for example.
DESCRIPTION OF RELATED ART
[0002] U.S. Pat. No. 6,651,996 to Allemang discloses a support device is provided for supporting a wheeled vehicle, such as a motorcycle, in a substantially upright position on a supporting surface. The support device comprises a wheel engaging section to contact and hold a wheel of the vehicle. The wheel engaging section is coupled to a lateral support beam which contacts the supporting surface to resist tilting of the wheeled vehicle. In one embodiment, the lateral support beam is removable from the wheel engaging section to facilitate storing or transporting the support device
[0003] U.S. Pat. No. 5,735,410 to Kallstrom discloses a stand for locking the front wheel of a vehicle, such as a motorcycle, in a stable position. The stand has front and rear support mechanisms which, in a preferred embodiment, are actuated by a ramp so that the weight of the front wheel of the motorcycle as it is rolled onto the ramp will actuate the front and rear supports to engage the tire at locations forward and rearward of the wheel axis of rotation.
[0004] Neither of these references disclose a simple, easy to use, support for a motorcycle that may be used on various terrains.
SUMMARY OF THE INVENTION
[0005] The present invention is an apparatus for supporting a motorcycle consisting of at least one pair of support arms for receiving a tire of the motorcycle which connect to a horizontal crosspiece for receiving the support arms. A vertical support member is affixed to the horizontal crosspiece which supports the tire. A horizontal support means affixed to the vertical support member is sized for receipt in a trailer hitch.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] FIG. 1 discloses a side view of a motorcycle tire supported by the apparatus of the invention.
[0007] FIG. 2 is an overhead view of the apparatus of FIG. 1 .
[0008] FIG. 3 is a overhead view of a second embodiment of the apparatus of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0009] FIG. 1 discloses a side view of the invention 10 supporting the rear tire of a motor cycle. FIGS. 1 and 2 disclose the simplest embodiment of the invention 10 wherein support arms 30 are mounted on crosspiece 20 . Crosspiece 20 may be affixed by means of boltholes (not shown) to any structure, such as the frame of a garage. However, in other applications, additional structure is required. Referring again to FIGS. 1 and 2 , horizontal support means 50 is attached directly to crosspiece 20 . The distal end of horizontal support means 50 is sized to be nestingly received in a trailer hitch mounted on any vehicle. In this embodiment, crosspiece 20 is a 1½ inch solid steel bar of approximately 11 inches in length. Support arms 30 are 1½ inch solid steel bars, and are sized to be permanently mounted on crosspiece 20 such that support arms extend about 11 inches from crosspiece 20 . Support arms 30 angle slightly from the perpendicular to crosspiece 20 , being mounted approximately 4½ inches at the point of attachment and being about 6½ inches apart at their distal end. The means of mounting support arms 30 to crosspiece 20 is not a limitation of the invention. They may be either welded or bolted to crosspiece 20 . Although cross piece 20 and support arms 30 have been described and solid steel bars, they may be constructed of hollow tubing in the interests of reducing weight.
[0010] In order to accommodate a variety of vehicles whose trailer hitches may be at differing distances to the ground, vertical support means 55 is permanently affixed to horizontal support 50 to adjustable receive vertical support member 40 . Vertical support means 55 is a hollow cylinder of about 6 inches in length which slideably receives vertical support member 40 which moves vertically through vertical support means 55 . Vertical support means 40 may also serve as an abutment to tire 1 , restraining the motorcycle from rolling. Vertical support means 55 has a through hole 58 drilled perpendicular to the longitudinal axis of horizontal support 50 to receive a 2 inch locking pin 15 . Vertical support member 40 is permanently affixed to crosspiece 20 , with a plurality of through holes 48 drilled on opposing sides of vertical support member 40 along its vertical axis, parallel to crosspiece 20 , and positioned to be aligned with through hole 58 . Vertical support member 40 may then be adjusted to any height above the ground by matching through hole 58 to any of the various through holes 48 , and inserting lock pin 15 .
[0011] Motorcycle tire 1 is locked to apparatus 10 by locking means consisting of chain 35 extending through motorcycle tire 1 , and attached at either end at eyehooks 32 attached at opposing sides of support arms 30 . Alternatively, locking means could consist of a solid bar removably and adjustably mounted between the support arms 30 , or by any other means readily apparent to one of ordinary skill in the arts, including locking means attached to crosspiece 20 .
[0012] A second embodiment of the invention is disclosed in FIG. 3 , wherein two sets of support arms 30 are mounted on crosspiece 20 in order to simultaneously support two motorcycles. In this embodiment, crosspiece 20 is approximately 42 inches in length, with approximately 30 inches between each pair of support arms 30 . The number of pairs is not a limitation of the invention, and the crosspiece 20 could easily support three pairs of support arms. As with the first embodiment of the invention, vertical support means 55 is permanently affixed to horizontal support 50 to adjustable receive vertical support member 40 . Vertical support means 55 is a hollow cylinder of about 6 inches in length which slideably receives vertical support member 40 which moves vertically through vertical support means 55 . Vertical support means 40 may also serve as an abutment to tire 1 , restraining the motorcycle from rolling. Vertical support means 55 has a through hole 58 drilled perpendicular to the longitudinal axis of horizontal support 50 to receive a 2 inch locking pin 15 . Vertical support member 40 is permanently affixed to crosspiece 20 , with a plurality of through holes 48 drilled on opposing sides of vertical support member 40 along its vertical axis, parallel to crosspiece 20 , and positioned to be aligned with through hole 58 . Vertical support member 40 may then be adjusted to any height above the ground by matching through hole 58 to any of the various through holes 48 , and inserting lock pin 15 . Concomitantly, each pair of support arms 30 has a means of locking tire 1 to the support of the invention.
[0013] While the present description contains much specificity, this should not be construed as limitations on the scope of the invention, but rather as examples of some preferred embodiments thereof. For example, the apparatus has been described as constructed from generally rectangular or square cross-sectional steel. The cross-sectional shape should not be a limitation on the invention. Thus, cylindrical cross-sectional shapes are also contemplated to be within the scope of the invention. And, although welding is considered to produce a more sturdy structure, the parts of the invention could easily be designed by one of ordinary skill in the mechanical arts to be bolted tog ether. Accordingly, the scope of the invention should not be determined by the specific embodiments illustrated herein. The full scope of the invention is further illustrated by the claims appended hereto.
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An apparatus for supporting a motorcycle on all terrains, and more particularly, a means of supporting the tire of a motorcycle in an upright position.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to child car seat devices and methods therefor, and more specifically relates to devices for cooling the hot surface of a child car seat and buckling apparatus or warming the cold surface of a child car seat and buckling apparatus so as to make the child car seat comfortable and safe for a child and a method therefor.
2. Description of the Related Art
In hot temperatures, the surface area of a child car seat, including the buckling apparatus, can become very hot. Unless these areas are cooled before a child is placed in the car seat, the child will be uncomfortable and may possibly be burned by the hot surface of the car seat or the metal or plastic buckling apparatus.
In the past, a number of devices have been used to attempt to alleviate this problem. For example, U.S. Pat. No. 5,150,945 issued to Aupperlee, et al. discloses a removable child seat cover, to be placed over a car seat when not in use and to be removed before placing the child into the car seat. The removable cover disclosed in Aupperlee, et. al. is placed over the child car seat when not in use, so as to protect the car seat surface from direct exposure to the sunlight. For example, a user going on a shopping trip with a small child would travel to the shopping center with the child restrained in the car seat, remove the child from the car seat upon arriving at the shopping center, place the cover on the car seat after removing the child, and then remove the cover after returning to the car before placing the child into the car seat for the drive away from the shopping center.
While removable covers of this type provide some short-term benefit in terms of limiting the amount by which the surface of the car seat will heat up when exposed to direct sunlight, even a covered car seat can become significantly hot where the temperature outside of the car is sufficiently high and the car windows have been closed. Indeed, after a period of time, the length of which depends on the temperature inside the car, removable covers of the type disclosed in Aupperlee cease to providing any meaningful cooling benefit. Moreover, a removable car seat of the type disclosed in Aupperlee, et al. cannot be used to rapidly cool a car seat that is already hot because the car seat has been left directly exposed to sunlight. Thus, if the user forgot to place the cover over the car seat before leaving the car--e.g., if the user forgot to place the cover over the car seat after taking the child from the car to go shopping--the cover would be of no use in cooling down the hot car seat upon the user's return to the car.
Accordingly, there existed a need to provide an improved car seat cooling device and method that would be able to cool down a hot car seat surface--as opposed to merely limiting the amount by which the car seat surface will heat up when exposed to direct sunlight. Moreover, the improved car seat cooling device and method must also be able to cool down the car seat's buckling apparatus, the metal parts of which can become extremely hot and dangerous under certain circumstances. Because the cooling device must be used by a person who often will be holding a child, and because the cooling device must be removed from the car seat before a child is placed therein, the improved cooling device must be capable of being removed by the user with only one hand. Additionally, because the cooling device will typically be transported inside of a car where space is at a premium, the cooling device must be able to be secured in a limited space--ideally in a rolled-up position.
Although perhaps less dangerous, a car seat surface that has become extremely cold because of exposure to cold weather can also be a source of discomfort to a child. Removable car seat covers of the type disclosed in Aupperlee, et al. are of no benefit in this kind of situation. Thus, a need existed for a device to warm the cold surface area of a car seat and buckling apparatus, so as to make that surface area more comfortable and inviting to a child. The car seat warming device, like the improved car seat cooling device, must be capable of being removed by the user with only one hand and must be able to be to be secured in a limited space.
SUMMARY OF THE INVENTION
In accordance with one embodiment of this invention, it is an object of this invention to provide an improved, removable, child car seat temperature control device and method.
It is another object of this invention to provide an improved, removable, child car seat temperature control device and method that is capable of cooling down a hot car seat surface, including a car seat buckling apparatus.
It is yet another object of this invention to provide an improved, removable, child car temperature control device and method that is capable of warming a cold car seat surface, including a car seat buckling apparatus.
It is a further object of this invention to provide an improved, removable, child car seat temperature control device and method that may be removed from a car seat with one hand.
It is a still further object of this invention to provide an improved, removable, child car seat temperature control device that may be rolled-up for storage when not in use.
It is still another object of this invention to provide an improved, removable, child car seat temperature control device and method whereby the device can be rapidly and securely attached to a child car seat and/or quickly detached therefrom.
BRIEF DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with one embodiment of this invention, a removable child car seat cooling device is disclosed. The removable child car seat cooling device comprises, in combination: covering means for covering substantially all of a top surface of a seat portion and all of a top surface of a head and backrest portion of a child car seat, the covering means having a top surface and a bottom surface wherein the bottom surface contacts the top surface of the seat portion and the top surface of the head and backrest portion of the child car seat; cooling means coupled to the bottom surface of the covering means for cooling the top surface of the seat portion and the top surface of the head and backrest portion of the child car seat; and means for removably securing the covering means to the car seat.
In accordance with another embodiment of this invention, a removable child car seat warming device is disclosed. The removable child car seat warming device comprises, in combination: covering means for covering substantially all of a top surface of a seat portion and all of a top surface of a head and backrest portion of a child car seat, the covering means having a top surface and a bottom surface wherein the bottom surface contacts the top surface of the seat portion and the top surface of the head and backrest portion of the child car seat; warming means coupled to the bottom surface of the covering means for warming the top surface of the seat portion and the top surface of the head and backrest portion of the child car seat; and means for removably securing the covering means to the car seat.
In accordance with a further embodiment of the present invention, a method for cooling a child car seat is disclosed. The method comprises the steps of: providing covering means for covering substantially all of a top surface of a seat portion and all of a top surface of a head and backrest portion of a child car seat, the covering means having a top surface and a bottom surface wherein the bottom surface contacts the top surface of the seat portion and the top surface of the head and backrest portion of the child car seat; providing cooling means coupled to the bottom surface of the covering means for cooling the top surface of the seat portion and the top surface of the head and backrest portion of the child car seat; and providing means for removably securing the covering means to the car seat.
In accordance with yet another embodiment of the present invention, a method for cooling a child car seat is disclosed. The method comprises the steps of: providing covering means for covering substantially all of a top surface of a seat portion and all of a top surface of a head and backrest portion of a child car seat, the covering means having a top surface and a bottom surface wherein the bottom surface contacts the top surface of the seat portion and the top surface of the head and backrest portion of the child car seat; providing cooling means coupled to the bottom surface of the covering means for cooling the top surface of the seat portion and the top surface of the head and backrest portion of the child car seat; providing means for removably securing the covering means to the car seat; freezing the cooling means; securing the covering means to the car seat; leaving the covering means secured to the car seat until the car seat has been sufficiently cooled; and removing the covering means from the car seat.
The foregoing and other objects, features, and advantages of the invention will be apparent from the following, more particular, description of the preferred embodiments of the invention, as illustrated in the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a break-away type of perspective view of the preferred embodiment of a removable car seat temperature control device, as shown prior to placement on a child car seat.
FIG. 2 is a rear view of the preferred embodiment of a removable car seat temperature control device.
FIG. 3 is a cross-sectional side view of the removable car seat temperature control device of FIG. 2 taken along line 3--3.
FIG. 4 is a cross-sectional view of one of the pockets containing cooling or warming material, taken along line 4--4 of FIG. 3.
FIG. 5 is a perspective view of the removable car seat temperature control device of the present invention in a rolled-up position for storage.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to FIGS. 1 and 2, a removable child car seat temperature control device 10 having a top surface and a bottom surface is provided. The top surface of the temperature control device 10 is comprised of a seat portion 12 and a head and backrest portion 14, while the bottom surface of the temperature control device 10 has a corresponding seat portion 12a and head and backrest portion 14a. The seat portion and head and backrest portion of the temperature control device 10 substantially correspond in size and dimension to the seat portion 12b and head and backrest portion 14b of a child car seat 10a, with the seat portion 12a of the device 10 being fitted to contact and cover the seat portion 12b of the car seat 10a and the head and backrest portion 14a of the device 10 being fitted to contact and cover the head and backrest portion 14b of the car seat 10a. Side portions 16 are preferably located on both sides of the seat portion 12 and the head and backrest portion 14 of the device 10, while the bottom surface of the temperature control device 10 has corresponding side portions 16a. The side portions 16 of the temperature control device 10 substantially correspond in size and dimension to the side portions 16b of the child car seat 10a. Flap 18 of the device 10 extends below seat portion 12 and side portions 16 and, from the end of flap 18, a storage or tie-up type strap 20 is attached thereto. Located at the upper end of the head and backrest portion 14 of the device 10 is a device removal or gripping handle 22. The device 10 is preferably comprised of a quilted fabric, which fabric has insulating air pockets which help maintain the cooling or warming effect of the device 10.
Car seat 10a features one type of a buckling apparatus 26. There are different styles and shapes of car seat buckling apparatuses. The buckling apparatus 26 shown in FIG. 1 is a typical variety, whereby a buckle insert 28 is secured to a car seat 10a with straps 30. Buckle insert 28 may be inserted into one of a plurality of buckle receiving apertures 34 located in the seat portion 12b of the car seat 10a. Often, the buckling apparatus 26 includes a relatively large padded member 32 as shown in FIG. 1. In another common variety of child car seat, the large padded member 32 is not featured or used. In child car seats of this design, a post (not shown) is located substantially where the buckle receiving apertures 34 of car seat 10a are located, and this post contains a buckle receiving aperture to receive the buckling apparatus' buckle insert.
As shown in FIG. 2, preferably a flap 36 extends outwardly from the head and backrest portion 14 of the device 10, which flap 36 extends around the curved outer side portions 16a of the child car seat 10a for rapid attachment of the temperature control device 10. Located at the edge portions of the flap 36 for attachment around the edge portion of the side portions 16 is an elastic band 24, for removably securing the temperature control device 10 to a child car seat 10a. A substantially rectangular area 36a is cut out of the top portion of the flap 36, which area 36a must be sufficiently large to allow the large padded member 32 (or equivalent structure) to pass therethrough and be inserted into the temperature control device 10 (see FIG. 3). The elastic band 24 extends continuously around the edges of the side portions 16 because of attachment to the flap 36, including across the bottom of the open rectangular area 36a, so as to maintain the temperature control device 10 securely in position over the car seat 10a.
As shown in FIGS. 2 and 3 and in phantom in FIGS. 1 and 2, a plurality of substantially rectangular pockets 38 are sewn into or otherwise attached or coupled to the bottom surface of the temperature control device 10; i.e., to seat portion 12a and to head and backrest portion 14a. Preferably, four pockets 38 are coupled to the head and backrest portion 14a, while two pockets 38 are coupled to the seat portion 12a. A plurality of substantially square pockets 38a are preferably also sewn into or otherwise attached or coupled to side portions 16a; however, the device 10 will retain a substantial portion of its effectiveness without pockets 38a . Preferably, four pockets 38a are located on side portions 16a adjacent the smaller ends of the pockets 38 that are coupled to the seat portion 12a, and four pockets 38a are located on side portions 16a adjacent the smaller ends of the two pockets 38 that are coupled to the head and backrest portion 14a and that are nearest the seat portion 12a. Within each of the pockets 38 and pockets 38a is located a packet 40 and a packet 40a, respectively, of cooling material or warming material. For example, the packets 40 and packets 40a may contain a refreezable cooling material or a reheatable warming material, such as the cooling and heating gell packs marketed under the name POLAR BEAR ICE. The packets 40 and packets 40a may also contain a one-time heating material. The pockets 38 and 38a are preferably sewn shut so that the packets 40 and packets 40a are essentially permanently enclosed therein, or the pockets 38 and 38a may be resealable--using a hook and loop, zipper, or equivalent fastening-type device or structure--so that the packets 40 and packets 40a may be individually removed from the device 10 for reheating, refreezing, or replacement.
Referring specifically to FIG. 3, a pocket or cavity area 42 is located between the head and backrest portion 14a and the pockets 38, so that the buckling apparatus 26 may be inserted therein. In this manner, the buckling apparatus 26 will be cooled or warmed by the packets 40 in the same manner as the surface of the car seat 10a during use of the temperature control device 10. The pocket 42 may be created in a number of different ways, including by securing only the short sides of the pockets 38 to the head and backrest portion 14a, as well as securing the long side of the fourth pocket 38 from the top of the head and backrest portion 14a that abuts the gap between the four pockets 38 behind head and backrest portion 14a and the two pockets 38 behind seat portion 12a--while leaving the remaining portions of the four pockets 38 behind head and backrest portion 14a unattached to the head and backrest portion 14a.
Statement of Operation
A person wishing to use the temperature control device 10 to cool the surface of the car seat 10a will first need to freeze (or at least substantially cool) the material located within the packets 40 and the packets 40a. This may be accomplished by placing the entire temperature control device 10 into a freezer or, if the packets 40 and packets 40a are removable from the pockets 38, by placing just the packets 40 and the packets 40a into the freezer. Once the packets 40 and the packets 40a are sufficiently cooled, the temperature control device 10 is ready to be used.
The next step is to place the temperature control device 10 over the car seat 10a, with the head and backrest portion 14, the seat portion 12, and the side portions 16 of the temperature control device 10 corresponding to the same portions of the car seat 10a. The temperature control device 10 is secured into position on the car seat 10a with the elastic strap 24. The buckling apparatus 26, including the relatively large padded member 32 and the buckle insert 28 is then inserted through the rectangular area 36a and into the pocket 42 between the pockets 38 and the head and backrest portion 14a.
The temperature control device 10 is left on the car seat 10a until the surface of the car seat 10a and the buckling apparatus 26 reach the desired temperature. The temperature of the surface of the car seat 10a and the buckling apparatus 26 can be checked by simply inserting a hand under the temperature control device 10a and manually checking the surface temperature of the car seat 10a and/or that of the buckling apparatus 26, or the user can simply leave the device 10 on the car seat 10a for a specified period of time. Tests have indicated that the surface temperature of the car seat 10a can be substantially reduced in as little as one minute with the use of the device 10. In one test, the temperature of a car seat surface was cooled more than 25 degrees Fahrenheit in just one minute. Thus, a user could simply leave the device 10 on the car seat 10a for one minute, after which time the car seat 10a will be sufficiently cooled to be occupied by a child.
Once the desired temperature has been achieved, the user may remove the temperature cooling device 10 with one hand by simply grasping the handle 22 and pulling the temperature cooling device 10 off of the car seat 10a. After the child has been secured in the car seat 10a, the temperature control device 10 may be stored by rolling it and then securing it in a rolled up position with the storage strap 20, as shown in FIG. 5. Storage strap 20 may either be a one-piece elastic loop that can be stretched over an end of the rolled-up temperature cooling device 10 or it may be a one or two piece strap with an attaching hook and loop assembly.
The temperature control device 10 may be reused, without first refreezing the packets 40 and packets 40a, as long as the packets 40 and packets 40a remain cold. Tests have indicated that where the material in the packets 40 and 40a has been frozen and the device 10 is kept in a rolled up position, the packets 40 and 40a maintain a substantial portion of their cooling ability over a more than eight hour period. To extend the use of the temperature control device 10, it is also possible, although generally not necessary, to store it in a cooler or other insulated container that maintains the relatively cool temperature of the packets 40 and 40a. Thus, if the temperature control device 10 is first used to cool the car seat for a trip from the house to the store, it may be rolled up and left inside the care or placed in a cooler while the child is in the car seat, and then reused on the car seat while the parent and child are in the store so that the seat will be cool for the return trip to the house. Once the packets 40 and 40a are no longer sufficiently cold to cool the surface of the car seat 10a and the buckling apparatus 26, they must be refrozen again.
If the temperature control device 10 is to be used to warm the surface of a car seat 10a and a buckling apparatus 26, the packets 40 and 40a must contain a reheatable or, if desired, a one-time use warming material. The warming material in the packets 40 and 40a will operate, when the temperature control device 10 is placed over a car seat 10a, to heat the surface of the car seat 10a and the buckling apparatus 26. When the warming material in the packets 40 and 40a is no longer sufficiently warm, it must be reheated or, if it is a one-time use material, replaced. In all other respects, the operation and storage of the temperature control device 10 will be the same, whether the device is used for warming or cooling.
While the invention has been particularly shown and described with reference to the preferred embodiments thereof, it will be understood by those skilled in the art that the foregoing and other changes in form and details may be made therein without departing from the spirit and scope of the invention.
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A temperature control device for cooling a hot car seat surface is disclosed. The device comprises covering means for covering substantially all of the surface area of the car seat, a pocket or space for receiving a buckling apparatus, and cooling means for cooling both the car seat surface and buckling apparatus. The temperature control device may also be rolled up, readily stored, and reused. The temperature control device may also be used to warm a cold car seat surface and buckling apparatus, by substituting warming material for cooling material in the device.
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This application is a division of application Ser. No. 640,731 filed Aug. 14, 1984, now issued as U.S. Pat. No. 4,670,428, which in turn is a continuation-in-part of application Ser. No. 344,309 filed Feb. 1, 1982, now abandoned, which in turn is a continuation of application Ser. No. 154,132 filed May 29, 1980, now abandoned.
FIELD OF THE INVENTION
The present invention relates to a method of treating convulsions, including convulsive tremors and convulsive seizures, and, in particular, epilepsy, with organic copper compounds.
BACKGROUND OF THE INVENTION
Copper is a normal component of the human brain, which contains about 370 mg of copper per gram of tissue ash. This amount of tissue copper ranks second only to that amount found in the liver, the storage organ for copper.
Normal brain development and function requires a number of copper-dependent enzymes. The following is a list of these enzymes and their role in brain function.
______________________________________Copper-Dependent Enzyme Role in Brain Function______________________________________(1) Cyctochrome c oxidase Cellular respiration(2) Cerebrocuprein (cerebral Dismutation of superoxide superoxide dismutase) anion radicals(3) Tyrosinase Conversion of tyrosine to DOPA(4) Dopamine-β-hydroxylase Conversion of dopamine to norepinephrine and epinephrine(5) Lysyl oxidase Conversion of procollagen to tropocollagen and proelastin to elastin in the vasculature______________________________________
In addition, copper-dependent processes are required for the modulation of prostaglandin syntheses, lysosomal membrane permeability, the activity of histamine, and myelinogenesis.
A variety of brain pathologic disorders accompanied by convulsive seizures are associated with abnormal copper metabolism in humans. Serum copper is elevated in epileptic patients, but brain copper levels are markedly reduced in autopsied epileptics. The elevated serum copper concentrations may indicate physiologic mobilation of copper from the liver to the brain in life but depleted stores leading to copper deficiency may account for decreased brain levels postmortem. Children with severe copper deficiency due to inadequate intake or Menkes' Syndrome, which includes depleted liver copper stores and markedly decreased brain copper levels, are known to have convulsive seizures as a constant feature of their copper deficiency. In addition, neonatal copper deficiency and the copper deficiency associated with Menkes' Syndrome are also associated with severe or terminal central nervous system disorders.
Seizures as well as neuronal and cerebral degeneration also occur in copper-deficient anaimals. Both quaking mice and mottled mice exhibit tremors as well as neural and central nervous system degeneration as symptoms of their genetic copper deficiency. Rats which are made copper-deficient by removing copper from their diet also exhibit convulsive tremors and central nervous system degeneration. The observation of seizures and central nervous system degeneration in association with a reduction in brain copper levels and concomitant reduction in norepinephrine and epinephrine levels which have been proposed to be seizure modulators, are consistent with known copper requirements [Jobe, P. C., A. L. Picchioni and L. Chin, Role of Brain Norepinephrine in Audiogenic Seizure in the Rat, J. Pharmac. Exp. Ther., 184: 1-10 (1973), hereby incorporated by reference]. Further, complexing agents which produce tremors in these animals also reduce brain copper levels [Hadzovic, S., R. Kosak and P. Stern, The Effect of Tremorigenic Substances on the Copper Content of the Rat Brain, J. Neurochem, 3: 1027-29 (1966); Price, T. R. and P. Silberfarb, Convulsions Following Disulfiram Treatment, Am. J. Psychiatry, 133: 235 (1976), hereby incorporated by reference]. Finally, lambs born to ewes living on copper deficient pastures have a poorly developed central nervous system and exhibit tremors. On recognition, this enzootic ataxia is prevented by injecting the pregnant ewes with copper complexes [Underwood, E. J., In: Trace Elements in Human and Animal Nutrition, 4th Ed. Academic Press, New York, pp. 56-108 (1977), hereby incorporated by reference].
Existing antiepileptic drugs have been found to be ineffective in treating many individuals with epilepsy. This is in part due to serious side effects associated with these agents which include: intolerance, sedation, gingival hyperplasia, ataxia, nystagmus, dipolpia, vertigo, psychoses, lethargy, euphoria, mydriasis, headache, hyperactivity, confusion, hallucinations, peripheral neuropathy, gastrointestinal irritation, vomiting, nausea, epigastric pain, anorexia, increased appetite, hypoglycemia, glycosuria, osteomalacia, symptoms of systemic lupus erythematosus, dermatoses, hepatic necrosis, many blood dyscrasias and lymphadenopathy [Woodbury, D. M. and E. Fingl, The Pharmacological Basis of Therapeutics, 5th Ed., MacMillan Pub., New York, pp. 201-225 (1975), hereby incorporated by reference]. Ataxia, anorexia [Underwood, E. J., In: Trace Elements in Human and Animal Nutrition, Id.], peripheral neuropathy, nystagmus, lethargy, and osteomalacia are associated with copper deficiency [Danks, D. M., Copper Transport and Utilization in Menkes' Syndrome and in Mottled Mice, Inorg. Persp. Biol. Med. 1: 73-100 (1977); Sorenson, J. R. J., Therapeutic Uses of Copper, In: Copper in the Environment, Ed. by J. O. Nriagu, John Wiley and Sons, New York, pp. 83-162 (1979); Underwood, E. J., In: Trace Elements in Human and Animal Nutrition, Id., hereby incorporated by reference].
SUMMARY OF THE INVENTION
The present invention seeks to overcome the problems and disadvantages of the prior art. As pointed out, supra, existing antiepileptic drugs are ineffective in treating many individuals with epilepsy because of their toxic side-effects. If drug-induced toxicities are in part caused by the removal of copper from some copper-dependent metalloprotein or metalloenzyme via complexation as a result of therapy, then these toxicities may be avoided by treatment with a copper complex of these drugs. Because copper complexes are known to have potent antiulcer activity and lack gastrointestinal irritant activity [Sorenson, J. R. J., Copper Chelates As Possible Active Forms of the Anti-Arthritic Agents, J. Med. Chem. 19(1): 135-147 (1976); Sorenson, J. R. J., Copper Complexes, A Unique Class of Antiarthritic Drugs, Prog. Med. Chem. 15: 211-260 (1978); and Walker, W. R., R. Reeves and D. J. Kay, Role of Cu 2+ and Zn 2+ in Physiological-Activity of Histamine in Mice, Search 6: 134-135 (1975), hereby incorporated by reference], it is conceivable that at least the gastrointestinal side-effects of the existing antiepileptic drugs may be circumvented by using copper complexes in therapy. If copper complexes of the antiepileptic drugs or other copper complexes have increased anticonvulsant activities and do not cause gastrointestinal irritation or the other toxicities associated with the currently used drugs they would offer more effective and less toxic therapy of convulsions and epilepsy.
Broadly, the present invention is directed to a method for treating convulsions, including convulsive tremors and convulsive seizures, and epilepsy comprising administration of a therapeutically effective amount of an organic compound of copper (in the cuprous or cupric form) having anticonvulsant and/or antiepileptic activity.
Such compounds include but are not limited to copper complexes of imines, including the following specific types of imines which possess distinctive configurations when complexed with copper: bisethyleneimine Schiff bases, salicylidene-amino acid Schiff bases and pyridoxylidene-amino acid Schiff bases.
Such compounds further include but are not limited to copper complexes of carboxylic acids. Included among these carboxylic acids are aryl carboxylic acids and also branched and unbranched aliphatic carboxylic acids, for example, those carboxylic acids with aliphatic chains of one to seven carbons in length. The aryl carboxylic acids include, but are not limited to, acylsalicylic acids and benzoic acids. When complexed with copper the carboxylic acids are called copper carboxylates.
The organic copper compounds useful in the practice of this invention also include copper complexes of amino acids. Two molecules of the same or different amino acid complex with one atom of copper to form a distinctive copper coordination compound. The twenty common amino acids as well as other less common amino acids are potentially useful.
The organic copper compounds that can be used in the invention include copper complexes of salicylic acid and substituted salicylic acids. Such salicylic acids form copper salicylates.
One of the remarkable aspects of Applicant's invention is the demonstration that copper complexes of salicylates, acylsalicylates and amino acids exhibit anticonvulsant and/or antiepileptic activity. To Applicant's knowledge, no one has ever reported that salicylates, acylsalicylates, or amino acids alone, i.e., not complexed with copper, have any anticonvulsant and/or antiepileptic. On the contrary, what is known is that salicylate and acetylsalicylate (aspirin) actually cause convulsions at high doses, making Applicant's discovery that copper complexes of these compounds have anticonvulsant activity all the more remarkable. Applicant's discovery further supports the suggestion of reduced toxicity of copper complexes of existing anticonvulsant (antiepileptic) drugs.
Also suitable for use in the practice of this invention are copper complexes of known anticonvulsant/antiepileptic compounds. Such compounds are of the following classes: hydantoins, barbiturates, desoxybarbiturates, iminostilbenes, acetylureas, succinimides, benzodiazepines, oxazolidinediones, sulfonamides and fatty acids (saturated or unsaturated) or mixtures of any of the foregoing compounds. Remarkably, it has been found that subcutaneous administration of copper complexes of certain of the known anticonvulsant drugs, specifically amobarbital, is free of side effects (hypnosis or sedation) associated with the non-copper-complexed form of the drug. The potential for elimination of side-effects associated with known anticonvulsant and antiepileptic drugs by using copper complexes thereof is a particularly important discovery.
BRIEF DESCRIPTION OF THE FIGURE
FIG. 1 graphically depicts the anticonvulsant activity versus time for Cu(II) (salicylate) 2 in preventing the Metrazol-induced seizure after giving 100 mg/kg subcutaneously (closed circles) and in preventing the Maximal Electroshock-induced seizure after giving 600 mg/kg subcutaneously (open circles).
DESCRIPTION OF THE INVENTION
Copper complexes were synthesized using reported methods [Sorenson, J. R. J., Copper Chelates As Possible Active Forms of the Anti-Arthritic Agents, Id.; U.S. Pat. No. 4,221,785 of Sorenson, J. R. J., hereby incorporated by reference].
The copper complexes were submitted to the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) which has an Antiepileptic Drug Development (ADD) program to screen compounds for anticonvulsant activity. Test compounds were either dissolved in 0.9% saline, or suspended in either 30% polyethylene glycol 400 in 0.9% saline or 0.2% suspending agent like polyoxyethylene glycol or Tween 80 in 0.9% saline prior to injection into male Carworth Farms #1 mice or Sprague-Dawley rats. Thus, compounds can be administered as solutions, suspensions or ointments. Unless otherwise specified, concentrations are percent by weight.
In Phase I identification of anticonvulsant activity, test compounds were given intraperitoneally (IP) at 30, 100, 300 and, in some cases, 600 milligrams per kilogram (mg/kg) of body weight and protection against Maximal Electroshock and/or Metrazol-induced seizures was determined 30 minutes, 4 hours, or later. Initial studies using the intraperitoneal route of administration demonstrated that copper complexes were effective as anticonvulsants but stimulation or depression (rotating rod toxicity) and lethality were occasionally observed at the highest doses given. Subsequently the routine protocol was modified and certain of the test compounds (see Tables, infra) re-evaluated following subcutaneous (SC) injection at periods of up to 8 hours post injection. Subcutaneous administration can be helpful in determining whether or not hypnotic activity can be distinguished from anticonvulsant activity based upon the decreased rate of absorption associated with this route of administration as opposed to the more rapid rate of absorption associated with IP administration. With this protocol none of the copper complexes so tested was found to be toxic in the rotating rod test and no deaths were observed, even at the highest doses given. In addition, some of these compounds were found to have anticonvulsant activity at doses less than 30 mg/kg and for prolonged periods of up to 6 to 8 hours post injection.
Compounds found to be effective only at 30 minutes are viewed as rapid in onset (due to rapid distribution to the central nervous system) and of short duration. Compounds that are effective only at 4 hours are viewed as slower in onset. Those compounds that are effective at both 30 minutes and 4 hours are viewed to be rapid in onset and of prolonged duration. Variability in onset and duration may be useful in the design of therapeutic regimens in which combinations of compounds are administered to a convulsant or epileptic patient.
Minimal anticonvulsant activity and the lack of toxicity were criteria required for Phase II studies, in which the time of peak anticonvulsant effect in the Maximal Electroshock and Metrazol-induced seizures, efficacy (ED 50 values for protection against the Maximal Electroshock and Metrazol-induced seizures), and lethality (LD 50 in 24 hours) were quantified. All statistics were obtained by probit analyses.
SEIZURE MODELS
Maximal Electroshock Seizure Test. Maximal electroshock seizures were elicited with a 60 cycle alternating current of 50 mA intensity (5-7 times that necessary to elicit minimal electroshock seizures) delivered for 0.2 seconds via corneal electrodes. A drop of 0.9% saline is instilled in the eye prior to application of the electrodes in order to prevent the death of the animal. Abolition of the hind limb tonic extension component of the seizure is defined as protection.
Subcutaneous Pentylenetetrazol (Metrazol) Seizure Threshold Test. Eighty-five mg/kg of pentylenetetrazol (produces seizures in greater than 97% of mice) was administered as a 0.5% solution subcutaneous in the posterior midline. The animal was observed for 30 minutes. Failure to observe even a threshold seizure (a single episode of clinic spasms of at least 5 seconds duration) is defined as protection.
Toxicity. The rotating rod was used to evaluate neurotoxicity. The animal was placed on a 1-inch diameter knurled plastic rod rotating at 6 revolutions per minute. Normal mice can remain on a rod rotating at this speed indefinitely. Neurologic toxicity is defined as the failure of the animal to remain on the rod for 1 minute and is due to either stimulation or depression of the central nervous system.
EXPERIMENTAL EXAMPLES
Copper Complexes of Acylsalicylates
The data obtained for a number of copper complexes of acylsalicylates following subcutaneous (SC) administration are presented in Table I. Cu(II) refers to the cupric form of the compound, that is, copper with a valency of +2. Structures I and II schematically depict the generic structure of an acylsalicylate copper complex (where R represents hydrogen, branched or unbranched lower alkyl, aryl, alkyl-aryl, or substituted alkyl or aryl groups; R" represents branched or unbranched lower alkyl, aryl, halogen, or branched or unbranched lower alkyl or aryl groups substituted with halogens or oxygen-containing substituents such as hydroxy or alkoxy or nitrogen-containing substituents such as amino or nitro; and L represents solvating or other ligands capable of bonding to copper as indicated, such as water, alcohols, amines, ethers, sulfoxides and other solvents and competing ligands). The nonsolvated form of copper complexes of acylsalicylates, i.e., in the absence of L, exhibits a central binuclear configuration (as in Structure I) characteristic of nonsolvated forms of copper complexes of carboxylic acids which associate with copper atoms via their carboxyl groups in a 4:2 (carboxylic acid:copper atom) ratio. When L is present, the copper complex can exist in either the binuclear configuration of Structure I or the mononuclear configuration of Structure II depending on the affinity of L for copper. ##STR1##
TABLE I______________________________________ANTICONVULSANT ACTIVITY (PHASE I)OF SOME COPPER COMPLEXES OF ACYLSALICYLATES Maximal % Electro-COMPLEX Copper Route shock Metrazol______________________________________Cu(II).sub.2 (adamantyl- 9 .sup. SC.sup.1 .sup. I.sup.2 A.sup.3 at 30salicylate).sub.4 and 300 mg/kg at 30 min.Cu(II).sub.2 (acetyl- 15 SC I A at 100salicylate).sub.4 and 300 mg/kg at 30 min. and 6 hrs.; A at 30, 100 and 300 mg/kg at 8 hrs.Cu(II) 11 SC I A at 300(acetylsalicylate).sub.2 mg/kg at(dimethylsulfoxide).sub.2 30 min.; A at 100 mg/kg at 4 hrs.Cu(II) 11 SC I A at 300(acetylsalicylate).sub.2 mg/kg at(pyridine).sub.2 30 min.; A at 100 and 300 mg/kg at 4 hrs.Cu(II).sub.2 (3,5-dibromo- 8.6 IP A at 100 A at 100acetylsalicylate).sub.4 mg/kg at mg/kg at 4 hrs. 30 min. SC A at 300 I mg/kg at 4 hrs.Cu(II).sub.2 (3,5-diiodo- 6.8 IP I A at 100acetylsalicylate).sub.4 mg/kg at(H.sub.2 O).sub.6 30 min. and 4 hrs. SC A at 300 A at 300 mg/kg at mg/kg at 4 hrs. 4 hrs. .sup. SC.sup.4 Not A at 105 tested mg/kg at 30 min.______________________________________ .sup.1 SC = Subcutaneous. .sup.2 Inactive at doses studied. .sup.3 Activity at doses and times indicated. .sup.4 Phase II data.
Cu(II) 2 (adamantylsalicylate) 4 was found to have anticonvulsant activity at 30 minutes following subcutaneous injection at 30 and 300 mg/kg. Cu(II) 2 (acetylsalicylate) 4 [alternatively called copper aspirinate or Cu(II) 2 (aspirinate) 4 ] was found to have activity at 30 minutes, 6 hours and 8 hours following subcutaneous injection of the entire range of doses studied. The dimethylsulfoxide and pyridine solvates of Cu(II)(acetylsalicylate) 2 were found to be effective at the higher doses studied at 30 minutes and 4 hours. None of these complexes was found to have rotating rod toxicity at any of the doses or times studied following subcutaneous injection. Cu(II) 2 (3,5-dibromoacetylsalicylate) 4 and Cu(II) 2 (3,5-diiodoacetylsalicylate) 4 were also effective in protecting against both models of seizure.
COPPER COMPLEXES OF SALICYLATES ##STR2##
A group of copper complexes of salicylates with the generic structures shown schematically by structures III and IV (where R" and L represent the same groups, substituents, and ligands described for Structures I and II) were also evaluated for their anticonvulsant activity. The nonsolvated form of copper complexes of salicylates, i.e., in the absence of L, exhibits a mononuclear configuration as in Structure III. When L is present, the copper complex can exist in either the mononuclear configuration of Structure III or the binuclear configuration of Structure IV depending on the affinity of L for copper.
As shown in Table II, Cu(II)(salicylate 2 ), Cu(II)(4-tertiarybutylsalicylate) 2 and Cu(II)(3,5-ditertiarybutylsalicylate) 2 were found to be effective at the higher doses studied and for prolonged periods of up to 4 hours. Cu(II)(salicylate) 2 (pyridine) 2 had activity representative of a compound with rapid onset. The 3,5-diisopropylsalicylate, 3,5-ditertiarybutylsalicylate, 3,5-dibromosalicylate and 3,5-dichlorosalicylate complexes are of special interest because they were effective in preventing both the Maximal Electroshock and Metrazol-induced seizures in Phase I studies. All of these complexes were also found to be free of rotating rod toxicity at all of the doses and time periods studied following subcutaneous injection. Also presented in Table II are data obtained for three 4-substituted salicylates, Cu(II)(4-nitro-salicylate) 2 , Cu(II)(4-aminosalicylate) 2 and Cu(II)(4-acetylaminosalicylate) 2 , which were also effective in preventing seizures. However, administration of Cu(II)(4-nitrosalicylate) 2 at 100 mg/kg, Cu(II)(4-aminosalicylate) 2 at 300 mg/kg and Cu(II)(acetylaminosalicylate) 2 at 600 mg/kg elicited rotating rod toxicity. Moreover, administration of Cu(II)(4-nitrosalicylate) 2 at doses higher than 100 mg/kg and Cu(II)(4-aminosalicylate) 2 at doses higher than 300 mg/kg caused death in some of the test groups. These deaths may have resulted from a hypnotic overdose.
TABLE II______________________________________ANTICONVULSANT ACTIVITY (PHASE I)OF SOME COPPER COMPLEXES OF SALICYLATES Maximal % Electro-COMPLEX Copper Route shock Metrazol______________________________________Cu(II)(salicylate).sub.2 19 .sup. SC.sup.1 .sup. I.sup.2 A.sup.3 at 30, 100 and 300 mg/kg at 30 min.; A at 300 mg/kg at 4 hrs.Cu(II)(salicylate).sub.2 -- IP I A at 300(pyridine).sub.2 mg/kg at 30 min.Cu(II).sub.2 14 SC I A at 300(4-tertiarybutyl- mg/kg atsalicylate).sub.2.1/2H.sub.2 O 30 min.; A at 300 and 600 mg/kg at 4 hrs.Cu(II)(3,5-diisopro- 13 SC A at 300 A at 30,pylsalicylate).sub.2 mg/kg at 100 and 4 hrs; 300 mg/kg A at 100 at 30 min.; and 300 A at 100 mg/kg at and 300 6 hrs.; mg/kg at A at 300 4 hrs.; mg/kg at A at 100 8 hrs. mg/kg at 6 hrs.; A at 100 and 300 mg/kg at 8 hrs.Cu(II)(3,5-ditertiary- -- IP A a 100 A at 30butylsalicylate).sub.2 mg/kg at and 100 4 hrs. mg/kg at 30 min. SC A at 300 A at 300 mg/kg at mg/kg at 4 hrs. 4 hrs.Cu(II) -- .sup. IP.sup.4 I A at(4-nitrosalicylate).sub.2 100.sup.3 mg/kg.sup.6 at 30 min.Cu(II) -- IP I A at 30,(4-aminosalicylate).sub.2 100 and 300.sup.5 mg/kg.sup.6 at 30 min.; A at 100 mg/kg.sup.6 at 4 hrs.Cu(II)(4-acetyl- -- IP A at 600.sup.5 I.sup.7aminosalicylate).sub.2 mg/kg at 30 min.Cu(II)(5-chloro- -- IP I A at 300salicylate).sub.2 mg/kg at 30 min. and 30 mg/kg at 4 hrs. .sup. IP.sup.8 Not A at 30 tested mg/kg at 6 hrs.Cu(II)(3,5-dibromo- -- IP A at 300 A at 30salicylate).sub.2 (H.sub.2 O).sub.3 mg/kg at mg/kg at 4 hrs. 30 min. and 100 mg/kg at 4 hrs. SC A at 300 A at 600 mg/kg at mg/kg at 4 hrs. 4 hrs.Cu(II)(3,5-dichloro- -- IP A at 600 A at 100salicylate).sub.2 (H.sub.2 O).sub.2 mg/kg at mg/kg at 4 hrs. 30 min. SC I A at 600 mg/kg at 4 hrs.______________________________________ .sup.1 SC = Subcutaneous. .sup.2 Inactive at doses studied. .sup.3 Activity at doses and times indicated. .sup.4 IP = Intraperitoneal. .sup.5 Rotating Rod toxicity. .sup.6 Lethal at higher doses. .sup.7 Lethal at 100 mg/kg at 4 hours. .sup.8 Phase II data.
PHASE II EVALUATION OF CU(II)(SALICYLATE) 2
The Phase I test data presented in Tables I, II (supra) and III (infra) were all obtained in a standardized protocol using routine doses and routine times for the qualitative evaluation of anticonvulsant effects of the compounds tested. The NINCDS-ADD Program Phase II follow-up evaluation of active compounds with low toxicity is a quantitation of the anticonvulsant activity and acute toxicity. The anticonvulsant activity is quantitated by determining the times of peak activity and ED 50 values in the Maximal Electroshock and Metrazol-induced seizures. The acute toxicity is quantitated by determining the 24-hour LD 50 value.
The first copper complex selected by the ADD Program for Phase II evaluation was Cu(II)(salicylate) 2 . The data presented in FIG. I show that the time of peak effect for the inhibition of Metrazol-induced seizures following subcutaneous administration of 100 mg/kg was 2 hours and the time of peak effect for the inhibition of Maximal Electroshock induced seizures was 7 hours following subcutaneous administration of 600 mg/kg.
These data point out that the times of peak effects were different from the time of routine evaluation in the Phase I tests and that the dose required to protect against the Maximal Electroshock-induced seizure was larger than the largest dose used in the routine Phase I test. The data plotted in FIG. 1 also show that there was a rapid onset of protection against the Metrazol-induced seizure which decreases over the extrapolated period of 7 hours. The onset of protection against Maximal Electroshock-induced seizure was slower but the activity was prolonged over the 24-hour period (37% inhibition at 24 hours) and beyond. The ED 50 values for protection against Maximal Electroshock and Metrazol-induced seizures were 360 mg/kg and 38 mg/kg, respectively. The LD 50 value for this compound was 441 mg/kg. This value was not much different from the ED 50 for protection against Maximal Electroshock-induced seizures but it was over 10 times the ED 50 for the prevention Metrazol-induced seizures.
These data show that while Cu(II)(salicylate) 2 was inactive in protecting against the Maximal Electroshock-induced seizure in routine Phase I studies, it was found to be active in protecting against this seizure when higher doses were used and the activity was evaluated at different time periods. As a result, inactivity in Phase I studies cannot be taken as evidence of no activity at any time period or higher doses. The possibility exists that these apparently inactive compounds may be active in protecting against seizures when the treatment protocol is modified to include prolonged pretreatment (i.e., longer periods of time after administration of a copper complex but before inducement of the seizure) and/or higher doses.
COPPER COMPLEXES OF AMINO ACIDS
A series of copper complexes of bidentate amino acids generically depicted by Structure V (where R represents the alpha substituents of the D or L amino acids, wherein D and L represent the configuration of the alpha carbon and where two of the same or two different amino acids form the complex and L represents solvating or other ligands such as water, alcohols, amines, ethers, sulfoxides and other solvents and competing ligands) and a copper complex of a tridentate amino acid (glutamic acid) were evaluated as anticonvulsants. The results are presented in Table III. ##STR3##
TABLE III______________________________________ANTICONVULSANT ACTIVITY (PHASE I)OF SOME COPPER COMPLEXES OF AMINO ACIDS Maximal % Electro-COMPLEX Copper Route shock Metrazol______________________________________Cu(II) 22 .sup. IP.sup.1 .sup. NT.sup.2 A.sup.3 at(L-threoninate) 30, 100 and(L-serinate) 300 mg/kg at 30 min. and 4 hrs.Cu(II) 24 IP NT A at 30,(L-threoninate) 100 and(L-alaninate) 300 mg/kg at 30 min. and 4 hrs.Cu(II) 20 IP NT A at 30,(L-valinate).sub.2 H.sub.2 O 100 and 300 mg/kg at 30 min. and 4 hrs.Cu(II) 20 IP NT A at 30,(L-threoninate).sub.2 H.sub.2 O 100 and 300 mg/kg at 30 min. and 4 hrs.Cu(II) 27 IP NT A at 30,(L-alaninate).sub.2 100 and 300 mg/kg at 30 min. and 4 hrs.Cu(II) 16 IP NT At at 30,(L-phenylalaninate).sub.2 100 and 300 mg/kg at 30 min.Cu(II) 20 IP NT At at 100(L-cystinate).sub.2 H.sub.2 O and 300 mg/kg at 30 min.Cu(II) -- .sup. SC.sup.1 NT A at 30,(L-serinate).sub.2 100 and 300 mg/kg at 30 min. and 4 hrs..sup.6Cu(II) -- IP .sup. I.sup.5 A at 300(L-tryptophanate).sub.2 and 600 mg kg at 30 min. and 4 hrs.Cu(II) -- SC I A at 600(L-glutamate).sub.2 mg/kg at 4 hrs. IP I A at 100.sup.7 mg/kg at 30 min; A at 30 and 100 mg/kg at 4 hrs.Cu(II) -- SC I I(L-leucinate).sub.2 IP I A at 100 mg/kg at 30 min. and A at 30 and 100 mg/kg at 4 hrs.Cu(II) -- SC I A at 300(L-isoleucinate).sub.2 and 600 mg/kg at 30 min. and 600 mg/kg at 4 hrs.Cu(II)(L-isoleucinate).sub.2 IP A at 600.sup.6 A at mg/kg at 100.sup.6 30 min. mg/kg at 30 min.______________________________________ .sup.1 Not Tested. .sup.2 Active at doses and times indicated. .sup.3 Rotating red toxicity observed with 300 mg/kg at 4 hrs. .sup.4 Inactive at 30, 100, 300 and 600 milligrams per kilogram at 30 min and 4 hrs. .sup.5 Rotating rod toxicity. .sup.6 Lethal at higher doses.
Cu(II)(L-threoninate)(L-serinate), Cu(II)(L-threoninate)(L-alaninate), Cu(II)(L-valinate) 2 , Cu(II)(L-threoninate) 2 and Cu(II)(L-alaninate) 2 were found to be effective against the Metrazol-induced seizure at all doses studied and at both time intervals, 30 minutes and 4 hours. Rotating rod toxicity was observed with the first four of these compounds but only at the highest dose studied (300 mg/kg) at the end of the 4-hour observation. Cu(II)(L-phenylalaninate) 2 and Cu(II)(L-cystinate) 2 were also effective against the Metrazol-induced seizure at all three doses studied but only at the shorter time period.
Cu(II)(L-serinate) 2 , Cu(II)(L-tryptophanate) 2 , Cu(II)(L-glutamate) 2 , Cu(II)(L-leucinate) 2 and Cu(II)(L-isoleucinate) 2 have also been found to have anticonvulsant activity. In all cases these compounds were found to be more effective following IP than SC administration but they were also more toxic following IP administration. This is consistent with a more rapid absorption of greater amounts of these compounds following IP administration. The lethality associated with higher doses of some of the compounds is consistent with the possibility that these animals had been given hypnotic overdoses. The isoleucine complex was unique because it inhibited both the Maximal Electroshock and Metrazol-induced seizures in these Phase I tests.
COPPER COMPLEXES OF IMINES
Copper complexes of imines were evaluated for their anticonvulsant activity. The types of imine compounds tested included copper complexes of the following: (a) salicylidene-amino acid Schiff bases, the generic structure of which is depicted by Structure VI (where R represents the alpha substituents of the D or L amino acids, D and L denoting the configuration of the alpha carbon; R" represents branched or unbranched lower alkyl, aryl or halogen groups, or branched or unbranched lower alkyl or aryl groups substituted with halogens, oxygen-containing groups, e.g., hydroxy or alkoxy, or nitrogen-containing groups, e.g., amino or nitro; and L represents solvating or other ligands capable of bonding to copper as indicated, such as water, alcohols, amines, ethers, sulfoxides, and other solvents and competing ligands); (b) bisethyleneimine Schiff bases, the generic structures of which are depicted by Structures VII and VIII (where R and R" represent branched or unbranched lower alkyl, aryl or halogen groups, or branched or unbranched lower alkyl or aryl groups substituted with halogens, oxygen-containing groups, e.g., hydroxy or alkoxy, or nitrogen-containing groups, e.g., amino or nitro; and L represents solvating or other ligands capable of bonding with copper as indicated such as water, alcohols, amines, ethers, sulfoxides, and other solvents and competing ligands); and (c) pyridoxylidene-amino acid Schiff bases, the generic structure of which is depicted by Structure IX (where R represents the alpha substituents of the D or L amino acids; D and L denoting the configuration of the alpha carbon; and L represents solvating or other ligands capable of bonding with copper as indicated such as water, alcohols, amines, ethers, sulfoxides, and other solvents and competing ligands). ##STR4##
TABLE IV______________________________________ANTICONVULSANT ACTIVITY (PHASE I)OF SOME COPPER COMPLEXES OF SALICYLIDENE-AMINO ACID AND BISETHYLENEIMINE SCHIFF BASES Maximal Electro-COMPLEX Route shock Metrazol______________________________________Cu(II) SC I A (slight) at 100Salicylidene-L- and 300 mg/kg.sup.2valinate at 4 hrs. IP I A at 100 mg/kg.sup.2 at 30 min. and 30 mg/kg.sup.2 at 4 hrs.Cu(II) SC I A (slight) at 600Salicylidene-L- mg/kg at 30 min.histidinate IP I ICu(II) SC A at 100 A at 100, 300'Bisacetylacetonethyl- mg/kg at and 600' mg/kgeneimine 30 min.; at 4 hrs. A at 100, 300' and 600' at 4 hrs.Cu(II) SC I Ibissalicylato- IP I A (marginal) atethyleneimine 300 and 600 mg/kg at 4 hrs.______________________________________ A = Active. I = Inactive at doses studied. IP = Intraperitoneal. SC = Subcutaneous. .sup.1 Rotating rod toxicity. .sup.2 Lethal at higher doses.
The data obtained with copper complexes of salicylidene-amino acid Schiff bases and bisethyleneimine Schiff bases are presented in Table IV. The majority of these copper complexes had weak activity. The salicylidene-L-valinate complex also caused lethality at higher doses. The bisacetylacetonethyleneimine complex was effective in preventing both Maximal Electroshock and Metrazol-induced seizures, but rotating rod toxicity, which may also have been due to hypnotic activity, was found at the higher doses studied.
The data obtained with copper complexes of pyridoxylidene-amino acid Schiff bases are presented in Table V. These data show that the pyridoxylideneglycinate complex protected against both types of seizure. The serinate, tryptophanate and threoninate complexes were more effective but only protected against the Metrazol-induced seizure. The phenylalaninate and valinate complexes had no activity.
Some of these complexes are as active or more active than existing antiepileptic drugs. Other potentially useful copper complexes of pyridoxylideneamino acid Schiff bases include complexes of the following: tyrosine, dihydroxyphenylalanine (DOPA), 5-hydroxytryptophan, glutamic acid, gamma aminobutyric acid, aspartic acid, and beta-alanine.
TABLE V______________________________________PHASE I ANTICONVULSANT DATA OFPYRIDOXYLIDENEAMINOACID COPPER COMPLEXES Challenge Seizure Model.sup.1Complex Route Time MES Metrazol______________________________________Cu(II)Pyridoxylidene- IP 30 min 300 100glycinate(H.sub.2 O).sub.1.5 4 hrs I ICu(II)Pyridoxylidene-L- IP 30 min I 100serinate(H.sub.2 O) 4 hrs I 100Cu(II)Pyridoxylidene-L- IP 30 min I 30tryptophanate(H.sub.2 O).sub.2 4 hrs I 30Cu(II)Pyridoxylidene-L- IP 30 min I 30threoninate(H.sub.2 O).sub.2 4 hrs I 30Cu(II)Pyridoxylidene-L- IP 30 min I Iphenylalaninate(H.sub.2 O).sub.2 4 hrs I ICu(II)Pyridoxylidene-L- IP 30 min I Ivalinate(H.sub.2 O) 4 hrs I I______________________________________ .sup.1 The numerical values are the lowest active doses in mg/kg of body weight; I = Inactive; MES = Maximal Electroshock.
COPPER COMPLEXES OF CARBOXYLIC ACIDS
Several copper complexes of carboxylic acids have been tested for their anticonvulsant activity. The carboxylic acids include branched and straight chain aliphatic carboxylic acids as well as aryl carboxylic acids. In their nonsolvated state (i.e, in the absence of L), such carboxylic acids form a characteristic binuclear complex of copper as schematically depicted by Structure X (where R represents alkyl, aryl, aryl-alkyl groups wherein substituents may be hydrogen, halogen, oxygen-containing, e.g., hydroxy or alkoxy, or nitrogen-containing, e.g., amino or nitro substituents; and L represents solvating or other ligands capable of bonding to copper as indicated such as water, alcohols, amines, ethers, sulfoxides, and other solvents and competing ligands). When L is present, the copper complex of the carboxylic acid can exist in either the binuclear configuration of Structure X or the mononuclear configuration of Structure X-A depending on the affinity of L for copper. It should be recalled from the section on copper complexes of acylsalicylates, supra, that these compounds are also carboxylic acids that complex with copper in the nonsolvated state to form a binuclear coordination compound and, when in the solvated state, complex with copper in either the binuclear or mononuclear configurations shown by Structures I and II, respectively. Similarly, fatty acids, which include saturated and unsaturated monocarboxylic acids of up to about C 19 in length, can complex in either the binuclear or mononuclear configurations in their solvated states. ##STR5##
Copper acetate, Cu(II) 2 (acetate) 4 , a binuclear copper complex of a C 2 , straight chain, aliphatic carboxylic acid, was evaluated for anticonvulsant activity in a test in which aspirin (not complexed with copper) was also evaluated. It is known that in high doses aspirin (and other salicylates) have toxic effects on the central nervous system, including convulsions [Goodman and Gilman (Eds.), The Pharmacological Basis of Therapeutics (1980), 6th ed., MacMillan, New York, p. 689].
As shown in Table VI, aspirin was found to be inactive at 30, 100, 300 and 600 mg/kg in both seizure models at both time intervals, 30 minutes and 4 hours. Because it was thought that a copper-containing compound injected subcutaneously at the same site as the site of subcutaneous Metrazol injection might somehow, through a direct interaction with Metrazol perhaps, prevent the induction of seizures with Metrazol, and as a result cause an apparent anticonvulsant effect, this aspect of administration was investigated.
TABLE VI______________________________________ANTICONVULSANT ACTIVITY OFASPIRIN AND COPPER ACETATE Seizure Model MaximalCompound Route Electroshock Metrazol______________________________________Aspirin IP .sup. I.sup.1 I.sup.1Cu(II).sub.2 (acetate).sub.4 SC* .sup. I.sup.1 A at 30, 100, 300 and 600 mg/kg at 30 min. and 4 hrs.Cu(II)(Metrazol)Cl.sub.2 IP I A at 30 mg/kg at 30 min. SC I A at 300 mg/kg at 4 hrs.Cu(II).sub.2 (acetate).sub.4 SC NT I.sup.1Cu(II).sub.2 (acetate).sub.4 IP I.sup.1,2,3 A at 30 mg/kg at 30 min..sup.4,3Cu(II).sub.2 (acetate).sub.4 IP NT A at 10 and 20 mg/kg at 30 min. and A at 5, 10 and 20 mg/kg at 4 hrs.Cu(II).sub.2 (acetate).sub.4 IG .sup. I.sup.1 I.sup.1______________________________________ A = Active; NT = Not Tested. IP = Intraperitoneal. SC = Subcutaneous at site different from injection of Metrazol. IG = Intragastric. *Same injection site used for injection of Metrazol. .sup.1 Inactive 30, 100, 300 and 600 mg/kg at 30 min. and 4 hrs. .sup.2 Rotating rod toxicity at 30, 100, 300 and 600 mg/kg. .sup.3 Lethal at 30, 100, 300 and 600 mg/kg at 4 hrs. .sup.4 Lethal at 100, 300 and 600 mg/kg at 30 min.
As shown in Table VI, Cu(II) 2 (acetate) 4 was active when injected at the same site as the site of Metrazol injection and the copper complex of Metrazol, Cu(II)(Metrazol)(Cl 2 ), had some anticonvulsant activity when injected at a site different from the site of Metrazol injection. In addition, the Metrazol complex produced no rotating rod toxicity at doses up to 600 mg/kg, which is remarkable since Metrazol is a potent central nervous system stimulant accounting for its seizure producing capacity. Such stimulation produces marked rotating rod toxicity.
The lack of anticonvulsant activity of Cu(II) 2 (acetate) 4 when it is given subcutaneously at an alternate site of injection is consistent with the lack of anticonvulsant effect following subcutaneous injection of either copper acetate or copper chloride at a site different from the site of Metrazol injection as reported previously [Sorenson et al., Anticonvulsant Activity of Some Copper Complexes, In: Trace Substances in Environmental Health-XIII, D. D. Hemphill, ed., University of Missouri Press, Columbia, Mo., pp. 360-367 (1979); U.S. patent application Ser. No. 344,309 filed Feb. 1, 1982]. There it was reported that no anticonvulsant activity was found with either copper acetate or copper chloride using doses of 50, 100 and 300 mg/kg at 0.75, 1.5 and 3 hours post subcutaneous injection at a site different from the site of Metrazol injection.
On the the other hand, the observation of anticonvulsant activity at a very low dose, 5 mg/kg, following intraperitoneal administration of Cu(II) 2 (acetate) 4 at a site different from the subcutaneous administration of Metrazol, suggests that copper acetate is effective in inhibiting Metrazol-induced seizures by some mechanism other than a direct interaction with Metrazol when the rate of absorption and the amount of compound absorbed from the site of administration is increased, as it is with intraperitoneal administration. Consistently, copper acetate was found to be inactive when administered orally, the route which is likely to provide the slowest rate of absorption and the smallest amount of compound absorbed, in comparison with the subcutaneous and intraperitoneal routes of administration. It may, however, be that a method of oral dosing can be developed to produce anticonvulsant activity following oral treatment with copper complexes using prolonged treatment or facilitating oral absorption.
Other copper complexes of carboxylic acids which have been tested for anticonvulsant activity are the following: (1) Cu(II) 2 (valproate) 4 , also known as Cu(II) 2 (dipropylacetate) 4 , which is the binuclear copper complex of valproic acid, a known anticonvulsant drug (valproic acid is a C 7 , branched chain, aliphatic carboxylic acid); (2) Cu(II) 2 (phenylacetate) 4 , a binuclear copper complex of an aliphatic carboxylic acid; and (3) Cu(II) 2 (benzoate) 4 , a binuclear copper complex of an aryl or aromatic carboxylic acid. The data obtained with these compounds are presented in Table VII. Cu(II) 2 (valproate) 4 and Cu(II) 2 (phenylacetate) 4 were effective in protecting against Metrazol-induced seizures while Cu(II) 2 (benzoate) 4 was effective in protecting against both Maximal Electroshock and Metrazol-induced seizures.
TABLE VII______________________________________ANTICONVULSANT ACTIVITY OFCOPPER COMPLEXES OF CARBOXYLIC ACIDS Seizure Model MaximalComplex Route Electroshock Metrazol______________________________________Cu(II).sub.2 IP I A at 100 mg/kg(valproate).sub.4 at 30 min. SC I A at 600 mg/kg at 4 hr.Cu(II).sub.2 IP I A at 300 mg/kg(phenylacetate).sub.4 at 4 hr..sup.1Cu(II).sub.2 IP A at 300 A at 30, 100.sup.1(benzoate).sub.4 mg/kg at and 300.sup.1 mg/kg 30 min..sup.1 at 30 min.______________________________________ .sup.1 Rotating rod toxicity at 300 mg/kg.
COPPER COMPLEXES OF KNOWN ANTICONVULSANT AND ANTIEPILEPTIC DRUGS
Numerous compounds are known to have anticonvulsant and antiepileptic activity. Some of the better known therapeutic agents, listed in Table VIII, fall into the following classes: hydantoins, barbiturates, desoxybarbiturates, iminostilbenes, acetylureas, succinimides, benzodiazepines, oxazolidinediones, sulfonamides and fatty acids. [See K. W. Leal and A. S. Troupin, Clinical Pharmacology of Anti-epileptic Drugs: A Summary of Current Information, Clin. Chem. 23: 1964-1968 (1977), hereby incorporated by reference.] Copper complexes of the foregoing anticonvulsant and antiepileptic drugs can be used in the practice of the present invention.
TABLE VIII______________________________________KNOWN ANTICONVULSANTAND ANTIEPILEPTIC DRUGSClass Example______________________________________Hydantoins Phenytoin (Dilantin) Desmethylmephenytoin Desethylethotoin 5-Ethyl-5-phenylhydantoinBarbiturates Phenobarbital Mephobarbital MetharbitalThiobarbiturates ThiopentalDesoxybarbiturates PrimidoneIminostilbenes CarbamazepineAcetylureas PhenacemideSuccinimides Desmethylmethsuximide Ethosuximide Desmethylphensuximide α-Methyl-α-phenylsuccinimideBenzodiazepines Chlorazepam Desmethyldiazepam Diazepam Chlorazepate Chlordiazepoxide OxazepamOxazolidinediones Desmethyltrimethadione DesmethylparamethadioneSulfonamides AcetazolamideFatty Acids Sodium Valproate______________________________________
The general structure of hydantoins, barbiturates and thiobarbiturates is depicted schematically by Structure XI. ##STR6##
For hydantoins, X represents --NH--, R and R' are branched or unbranched lower alkyl groups, aryl groups or branched or unbranched lower alkyl or aryl groups, which may be substituted with halogen or oxygen-containing (e.g., hydroxy or alkoxy) and nitrogen-containing (e.g., amino or nitro) substituents. L represents solvating or other ligands capable of bonding with copper as indicated such as water, alcohols, amines, ethers, sulfoxides and other solvents and competing ligands.
For barbiturates, X represents ##STR7## and R, R' and L are as described for hydantoins.
For thiobarbiturates, sulfur replaces oxygen in bonding to copper as illustrated for barbiturates.
For oxazolidinediones, X represents --O-- and R, R' and L are as described for hydantoins.
For succinimides, X represents --CH 2 -- and R, R' and L are as described for hydantoins.
For acetylureas, X represents NH 2 and is not bonded to carbon-5 to give an acyclic ligand. R, R' and L are as described for hydantoins.
For desoxybarbiturates the general structure is ##STR8## and R, R' and L are as described for hydantoins.
For iminostilbenes the general structures may be ##STR9## where R and R' are the same or as described for hydantoins and L is as described for hydantoins.
For benzodiazepines the general structure may be ##STR10## where R and R' are hydrogen, halogen or nitro substituents, R" is hydrogen, alkyl, or the amide group ##STR11## is replaced by a group yielding an amide group on hydrolysis in vivo, and L is as described for hydantoins. The bonding atom is Structure XV may be replaced with N-oxide, ##STR12## In Structure XVI, X may be an oxygen of an N-oxide. The C-3 carbon may also be substituted with a carboxyl or hydroxyl group.
For Sulfonamides, the general structure is ##STR13## where R represents aryl, alkyl-aryl, a heterocycle or substituted aryl, alkyl-aryl or heterocycle wherein the substituents are halogen or oxygen-containing (e.g., hydroxy or alkoxy) or nitrogen-containing (e.g., amino or nitro) substituents. R' may be H or the same as R. L is as described for hydantoins.
With the hypothesis that copper complexes of the antiepileptic drugs might be the active metabolites of these drugs, several copper complexes of known antiepileptic drugs were synthesized and tested for their anticonvulsant activity. The first series of tests were performed with the copper complex of amobarbital and the results indicated that the copper complex of this known anticonvulsant drug was a more potent anticonvulsant than sodium (Na) amobarbital. The data are presented in Table IX.
TABLE IX______________________________________COMPARISON OF THE SODIUM AND COPPERAMOBARBITAL ANTICONVULSANT IN THE MAXIMALELECTROSHOCK SEIZURE MODEL FOLLOWINGINTRAPERITONEAL INJECTION Number Average Pro- of Sleep tection.sup.1 Animals Dose in Time, AgainstCompound Treated mg/kg minutes Seizure______________________________________Na amobarbital 5 65 0 0Cu(II)(amobarbital).sub.2 5 65 16.sup.2 100______________________________________ .sup.1 Percent protected. .sup.2 All animals slept.
Subsequently, the anticonvulsant activity of copper complexes of dilantin, valproate, phenobarbital (and pyridine and imidazole solvates thereof), amobarbital, lorazepam, α-methyl-α-phenylsuccinimide, carbamazepine, clonazepam, oxazepam, 5-ethyl-5-phenylhydantoin, thiopental and diazepam was investigated in Phase I testing, and for those compounds found to be active, Phase II testing. The results are presented in Table X.
TABLE X______________________________________PHASE I AND SOME PHASE II ANTICONVULSANT DATAFOR COPPER COMPLEXES OF ANTIEPILEPTIC DRUGS Seizure Model.sup.1 Challenge Metra-Compound Route.sup.2 Time MES zol______________________________________Cu(II)(Dilantin).sub.2 IP 30 min 30 100(H.sub.2 O).sub.3 4 hrs 30 100Cu(II)(Dilantin).sub.2 .sup. IP.sup.3 4 hrs.sup.4 13 NT.sup.5(H.sub.2 O).sub.3Dilantin .sup. IP.sup.3 1 hr.sup.4 7 Poten- tiates Metra- zol sei- zuresCu(II).sub.2 (Valproate).sub.4 IP 30 min I 100 4 hrs I ICu(II).sub.2 (Valproate).sub.4 SC 30 min I I 4 hrs I 600Valproic Acid .sup. IP.sup.3 15 min.sup.4 272 149Cu(II)(Phenobarbital).sub.2 IP 30 min 30 5(H.sub.2 O).sub.5.5 4 hrs 30 5Cu(II)(Phenobarbital).sub.2 SC 30 min 30 30(H.sub.2 O).sub.5.5 4 hrs 30 30Cu(II)(Phenobarbital).sub.2 IP 30 min 30 5(H.sub.2 O).sub.3 4 hrs 30 5Cu(II)(Phenobarbital).sub.2 SC 30 min 30 30(H.sub.2 O).sub.3 4 hrs 30 30Cu(II)(Phenobarbital).sub.2 .sup. IP.sup.3 2 hrs.sup.4 16 10(H.sub.2 O).sub.3Cu(II).sub.n (Phenobarbital).sub.n SC 30 min 100 30(H.sub.2 O).sub.2n (H.sub.2 O).sub.3n 4 hrs 30 30Phenobarbital .sup. IP.sup.3 1 hr.sup.4 22 13Cu(II)(Phenobarbital).sub.2 IP 30 min 100 30(pyridine).sub.2 4 hrs 100 30Cu(II)(Phenobarbital).sub.2 SC 30 min I I(pyridine).sub.2 4 hrs 30 30Cu(II)(Phenobarbital).sub.2 .sup. IP.sup.3 2 hrs.sup.4 17 9(pyridine).sub.2Cu(II).sub.n (Phenobarbital).sub.n SC 30 min 100 30(pyridine).sub.2n (H.sub.2 O).sub.3n 4 hrs 30 30Cu(II).sub.n (Phenobarbital).sub.n SC 30 min 30 30(pyridine).sub.2n (H.sub.2 O).sub.3n 4 hrs 100 30Cu(II)(Phenobarbital).sub.2 IP 30 min 100 300(imidazole).sub.2 4 hrs 100 30Cu(II)(Phenobarbital).sub.2 SC 30 min I 100(imidazole).sub.2 4 hrs 100 100Na.sub.2 [Cu(II)(Pheno- IP 30 min 30 30barbital).sub.4 ](H.sub.2 O).sub.2 4 hrs 100 100Na.sub.2 [Cu(II)(Pheno- SC 30 min 30 30barbital).sub.4 ](H.sub.2 O).sub.2 4 hrs 30 100Na.sub.2 [Cu(II)(Pheno- .sup. IP.sup.3 6 hrs.sup.4 25 20barbital).sub.4 ](H.sub.2 O).sub.2Cu(II)(Amobarbital).sub.2 IP 30 min 300 30(H.sub.2 O).sub.2.5 4 hrs I ICu(II)(Amobarbital).sub.2 IP 30 min 100 100(H.sub.2 O).sub.2 4 hrs I ICu(II)(Amobarbital).sub.2 SC 30 min 300 100(H.sub.2 O).sub.2 4 hrs I ICu(II)(Amobarbital).sub.2 .sup. IP.sup.3 30 min.sup.4 87 87(H.sub.2 O).sub.2.5Amobarbital IP 30 min 30 100 4 hrs I IAmobarbital .sup. IP.sup.3 15 min.sup.4 45 53Cu(II)(Amobarbital).sub.2 IP 30 min 300 100(pyridine).sub.2 4 hrs 300 30Cu(II)(Amobarbital).sub.2 SC 30 min I 600(pyridine).sub.2 4 hrs 100 600Cu(II)(Amobarbital).sub.2 IP 30 min 600 300(imidazole).sub.2 4 hrs I ICu(II)(Amobarbital).sub.2 SC 30 min I I(imidazole).sub.2 4 hrs I 600Cu(II)(Lorazepam).sub.2 IP 30 min 20 I(Cl).sub.2 H.sub.2 O 4 hrs 30 ICu(II)(Lorazepam).sub.2 SC 30 min 20 I(Cl).sub.2 H.sub.2 O 4 hrs 100 ILorazepam .sup. IP.sup.3 1 hr.sup.4 24 0.02Cu(II)(Diazepam).sub.2 (Cl).sub.2 IP 30 min 30 30 4 hrs 30 30Diazepam .sup. IP.sup.3 1 hr.sup.4 19 0.17Cu(II)α-methyl-α-phenyl- IP 30 min 100 100succinimide(H.sub.2 O).sub.0.75 4 hrs I 100Cu(II)α-methyl-α-phenyl- SC 30 min 30 30succinimide(H.sub.2 O).sub.0.75 4 hrs 100 600Cu(II)Carbamaze- IP 30 min 10 30pine(H.sub.2 O).sub.2 4 hrs 100 ICu(II)Carbamaze- SC 30 min 30 300pine(H.sub.2 O).sub.2 4 hrs 100 300Carbamazepine .sup. IP.sup.3 -- 9 Poten- tiates Metra- zol sei- zuresCu(II)(Clonazepam).sub.2 (Cl).sub.2 IP 30 min 10 1 4 hrs I 1Cu(II)(Clonazepam).sub.2 (Cl).sub.2 SC 30 min 1 1 4 hrs 30 1Cu(II)(Clonazepam).sub.2 (Cl).sub. 2 .sup. IP.sup.3 30 min.sup.4 25 0.05 (30 1 min).sup.4Clonazepam .sup. IP.sup.3 -- 19 0.2Cu(II)oxazepam IP 30 min 10 1 4 hrs I 10Cu(II)5-ethyl-5-phenyl- IP 30 min 100 300hydantoin(H.sub.2 O).sub.2.5 4 hrs 100 100Cu(II)5-ethyl-5-phenyl- SC 30 min 100 30hydantoin(H.sub.2 O).sub.2.5 4 hrs 30 100Cu(II)5-ethyl-5-phenyl- IP 30 min 100 100hydantoin(CH.sub.3 OH) 4 hrs 100 ICu(II)5-ethyl-5-phenyl- SC 30 min 100 100hydantoin(CH.sub.3 OH) 4 hrs 30 300Cu(II)5-ethyl-5-phenyl- IP 30 min 30 30hydantoin(HO)(Cl) 4 hrs I I(CH.sub.3 OH)Cu(II)(N--thiopental).sub.2 IP 30 min I I(H.sub.2 O).sub.2.5 4 hrs I ICu(II)(N--thiopental).sub.2 SC 30 min I I(H.sub.2 O).sub.2.5 4 hrs I 30Cu(II)(S--thiopental).sub.2 IP 30 min I I(H.sub.2 O).sub.2 4 hrs I ICu(II)(S--thiopental).sub.2 SC 30 min I I(H.sub.2 O).sub.2 4 hrs I I______________________________________ .sup.1 The numerical values are the lowest doses in milligrams per kilogram of body weight, I = inactive, MES = maximal electroshock. .sup.2 IP = intraperitoneal, SC = subcutaneous. .sup.3 Phase II data. .sup.4 Time of peak activity in Phase II studies and ED.sub.50 values for inhibition of seizures. .sup.5 Clonic seizures inhibited but animals stimulated by Metrazol (continuous running).
The data provided in Table X for the inhibition of Maximal electroshock and Metrazol-induced seizures are the lowest effective doses (mg/kg). If a compound is found to be effective and nontoxic in Phase I evaluations, which are done to detect anticonvulsant activity, it is further examined in Phase II studies to determine time of peak effect and ED 50 . Since Phase II evaluations are done only after Phase I, there are Phase II data for a smaller number of compounds. There are no Phase I data for the known anticonvulsant drugs since the NINCDS had no need to attempt to detect anticonvulsant activity for these established anticonvulsant agents. Phase II-ED 50 data for some of the compounds are included in Table X. Table X also contains Phase II time of peak effect data for the parent anticonvulsant drugs.
The copper complex of dilantin was found to have a rapid onset and prolonged duration in inhibiting only Maximal Electroshock-induced seizures. Dilantin is also known to only inhibit Maximal Electroshock-induced seizures but it potentiates Metrazol-induced seizures. The copper complex did not potentiate but did block both types of seizures. Phase II data for Cu(II)(dilantin) 2 indicate that it has a time of peak effect of 4 hours, which is longer than the time of peak effect for dilantin (1 hour).
In Phase I studies, Cu(II) 2 (valproate) 4 appeared to be ineffective against Maximal Electroshock seizures, but had some inhibitory activity against Metrazol-induced seizures. This compound had a rapid onset and short duration of activity following intraperitoneal administration and, consistently, a prolonged onset of activity at a higher dose following subcutaneous administration. The parent compound (valproic acid) was also weakly effective against Maximal Electroshock-induced seizures and more effective against Metrazol-induced seizures.
With few exceptions the phenobarbital complexes were also found to have rapid onset and prolonged durations of activity in both models of seizure. Although the data do not allow a rigorous comparison of these compounds, it is of interest that the pyridine and imidazole complexes were somewhat less effective than the aquo complexes. All three solvates had prolonged onsets of action following subcutaneous administration. The aquo phenobarbital complexes were most effective regardless of the route of administration and recent data show that the tri- and penta-aquo complexes are effective in preventing the Metrazol-induced seizure at a dose much lower than the lowest dose routinely used as the lowest dose in Phase I studies, 30 mg/kg. Activity at 5 mg/kg would appear to indicate greater activity than phenobarbital which has an ED 50 of 13 mg/kg.
Copper(II)(amobarbital) 2 complexes also appear to have rapid onsets and short durations of activity following intraperitoneal administration, which appears to be reversed with subcutaneous administration.
The copper complex of lorazepam appears to have a rapid onset of action and prolonged duration following intraperitoneal and subcutaneous administration. This complex appears to be quite active. However, this complex involves complexation at the 4-nitrogen and its stability may not be as high as others. The copper complex of diazepam also appears to have a rapid onset of action and prolonged duration following intraperitoneal administration.
Cu(II)α-methyl-α-phenylsuccinimide and Cu(II)5-ethyl-5-phenylhydantoin complexes were also effective in preventing both types of seizure with rapid onsets of action and prolonged durations of action following subcutaneous and intraperitoneal administration.
Cu(II)oxazepam also protected against both types of seizure and seems to be more prolonged in its action against Metrazol induced seizures.
The Cu(II)carbamazepine complex was also an effective anticonvulsant. However, it did not potentiate Metrazol seizures while the parent drug is known to be a seizure-inducing agent.
Cu(II)(clonazepam) 2 was found to be a very potent anticonvulsant. Doses less than those used in routine Phase I studies were required to obtain the lowest effective doses in both models of seizure. In addition, the results of Phase II studies with this complex show that the complex is four times as effective as the parent drug.
The copper complexes of thiopental were tested at lower doses than usually used in Phase I studies. It is anticipated that higher doses of these complexes will evidence anticonvulsant activity.
Since all of the foregoing drugs (parent compounds or ligands) are known to be active anticonvulsants, simultaneous comparisons of the ligands and their copper complexes are ultimately required to determine whether or not these complexes are more active than the ligands, as suggested by some of the data. Nevertheless, the data in Table X do indicate that all the copper complexes tested have anticonvulsant activity. Even if some of the copper complexes are not more active than the parent compound, they may nonetheless prove useful in therapy regimens alone or in conjunction with other complexes, especially if their time of peak effect differs from that of the parent and also especially if the copper complexes are less toxic and associated with fewer side effects than the parent compounds.
The foregoing experiments with copper complexes of acylsalicylates, salicylates, amino acids, imines, carboxylic acids and known anticonvulsant and antiepileptic drugs demonstrate that such complexes have anticonvulsant activity. That the intact copper complex may play a key role in the observed anticonvulsant activity is consistent with the observation that inorganic copper salts, which contain much more copper on a weight percentage basis, do not have anticonvulsant activity, or have less anticonvulsant activity based upon copper content, and also with the observation that there is a lack of an apparent direct correlation between the observed anticonvulsant activity of copper complexes and the amount of copper in them.
The organic compounds of copper or their solvates and other chemical modifications useful in the present invention can be administered as solid, solution, suspension, or ointment-dosing formulations in a concentration range of between about 0.01 to about 600 mg/kg of body weight and preferably between about 0.01 to about 100 mg/kg of body weight. The compounds can be administered orally, topically or parenterally, that is, intraperitoneally, subcutaneously or intravenously.
Having described the invention with particular reference to the preferred form thereof, it will be obvious to those skilled in the art to which the invention pertains after understanding the invention, that various changes and modifications may be made therein without departing from the spirit and scope of the invention as defined by the claims appended hereto.
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Copper-dependent enzymes are required for normal brain development and function. Copper deficiency can result in pathological disorders accompanied by convulsive seizures or tremors in man and animals. The present invention is directed to a method for treating convulsions or epilepsy comprising administration of a therapeutically effective amount of an organic compound of copper having anticonvulsant activity. Those compounds include copper complexes of carboxylic acids, acylsalicylates, salicylates, amino acids, imines and known anticonvulsant and antiepileptic drugs.
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PRIORITY
[0001] This application claims the benefit of German Patent Application No. 102015122069.5, filed on Dec. 17, 2015, which is hereby incorporated herein by reference in its entirety.
FIELD
[0002] The present invention relates to an injection device for administration of an injection to an animal, which comprises a main body and a contact device. The main body comprises an injection instrument and the contact device has a contact area which is shaped in conformity with a body part of an animal to which the injection is to be administered.
BACKGROUND
[0003] In the keeping and rearing of animals, it is often necessary to administer an injection to the animals. This can be carried out manually with a conventional syringe. In larger enterprises, for example in poultry farming, many animals are present, to which an injection has to be administered in as short a time as possible. Hence in the prior art there are injection devices by means of which an injection to an animal can be carried out more rapidly.
[0004] For example, U.S. Pat. No. 8,211,058 B2 discloses a device for injection into the breast muscle of a chicken. For this, the device has a pressure application surface which is matched to the anatomy of the chicken in the region of the breast muscle. Through the shaping of the pressure application surface, correct positioning of the bird is facilitated. In addition, three contact sensors are provided in the pressure application surface, which are activated on correct positioning of the chicken on the pressure application surface. If all three contact sensors are activated by the presence of the chicken, a control device triggers the injection into the breast muscle of the chicken.
[0005] However, there is a continuing need to provide an improved injection device for administration of an injection to an animal.
SUMMARY
[0006] The disclosure includes an injection device for administration of an injection to an animal. The device can include a main body with an injection instrument, a contact device, a support device, a force measurement device and a control device. The contact device comprises a contact area which is shaped in conformity with a body part of the animal to which the injection is to be administered. The support device supports the contact device on the main body movable in a pressure application direction. The force measurement device has at least one force sensor and is designed to measure the force (preferably in the pressure application direction) with which the contact device acts on the main body. The control device activates the injection instrument if the force measured by the force measurement device lies in the specified range.
[0007] The injection device serves in particular for the administration of a great variety of active substances which have to be administered subcutaneously and/or intramuscularly. For example by means of the injection device vaccines or medicaments can be administered to the animal. In particular, by means of the injection device medicaments for the treatment of a great variety of diseases can be administered.
[0008] The injection device, in particular the contact device, can be designed for the injection of a great variety of animals. The contact device is differently shaped depending on the animal to be treated (and optionally on its age). In particular, the injection device is intended for administration of an injection to poultry, such as for example chickens, ducks, turkeys, quail, geese, pigeons or other farmed poultry.
[0009] The main body may comprise in particular a housing and a stand device by means of which the injection device can be put down on a support. A recess in the housing, which for example provides an access to the injection instrument, can be closed by a cover. Furthermore, the control device is preferably arranged on or in the main body. In addition, a power supply such as for example a transformer or a battery can be provided for the injection instrument, the control device and/or the force measurement device. The injection instrument is in particular positioned in the main body, especially within the housing of the main body.
[0010] The injection instrument can be configured as a syringe, such as for example a self-filling syringe. The syringe can have a syringe cylinder, in which a plunger is movably located, and a cannula whereby by movement of the plunger in the direction towards the cannula the fluid present in the syringe cylinder (i.e. for example the vaccine or the desired medicament) can be discharged via the cannula. The injection instrument further preferably comprises an actuator which can move the syringe in the direction of the contact device, so that the cannula can be inserted into the part of the animal which is adjacent to the contact area, for example through an opening in the contact area. After this insertion process, the medicament or the active substance can then be administered by movement of the plunger. In particular, the cannula can be inserted into the breast muscle of the bird.
[0011] The injection instrument can include one or more syringes. In particular, it can have two syringes so that two different medicaments can be administered simultaneously to an animal.
[0012] The injection instrument can be designed such that the several syringes can be moved in the direction of the contact device simultaneously or independently of one another.
[0013] The injection instrument can however additionally or alternatively have any other type of injection device with which the desired injection can be administered to the animal lying against the contact area.
[0014] By means of the actuator, an end of the injection device on the discharge side can be moved to the animal lying against the contact area. Contact with the animal may or also may not be achieved. It is in particular essential that the desired injection can be carried out reliably.
[0015] The injection device can be configured such that the injection devices (e.g. syringes) are controllable independently of one another. Thus for example for a first injection procedure only one of the injection devices may be used. For a second injection procedure, two or more devices may then be used. During each injection procedure the relevant fluids (e.g. medicaments) can each be administered to several animals. The injection device can have an input interface via which the desired injection procedure is adjustable and/or selectable.
[0016] The contact area of the contact device can be shaped like the body part of the animal to which the injection is to be administered. For example, the injection can be administered into the breast muscle of a bird, in which case the contact area is then shaped like the breast of the bird. Alternatively, the contact device can be designed for injection into the neck or the foot of a bird. Then the contact area has a shape adapted thereto.
[0017] In particular, several contact devices can be assigned to the injection device, so that by means of one injection device injections can be administered to several different animal species or at different sites. For this, the contact device is in particular designed such that it can be detachably secured to the main body. The contact area of the contact devices is for example designed appropriately adapted with regard to the animal species, the animal breed, the age of the animal and/or the size of the animal.
[0018] The support device preferably makes it possible to secure the contact device to the main body, in particular detachably. The support device makes it possible for the contact device to be arranged movable on the main body, so that the contact device, preferably for the determination of the pressing force, can be moved towards the main body in a pressure application direction. This pressure application is in particular carried out in that the animal is pressed against the contact device and thereby the contact device is moved towards the main body.
[0019] The force measurement device can be provided to measure the force which the contact device exerts on the main body. In particular, the force measurement device serves to determine the pressing force of the animal against the contact device. The force measurement device is in particular provided on the main body. The contact device can thus be designed free from electrical components, since the force measurement device and also the control device is arranged on the main body. The contact device is thus in particular a pure molded component. The contact device can be produced by injection molding or deep-drawing.
[0020] The control device can for example be realized by means of a microprocessor or an electrical switching circuit. The control device activates the injection instrument, which for example takes place through the triggering of the actuator of the injection instrument, so that after the activation of the injection instrument, the needle is moved outwards from the main body and the injection preparation is conveyed through the needle.
[0021] The activation of the injection instrument can then take place when the measured force lies in a specified range. This means in particular that an injection is carried out if the pressing force of the animal against the contact device lies in a specified range. The specified range can for example comprise those forces which are greater than a specified threshold value. Alternatively the specified range can represent a lower and upper limit for the pressing force of the animal against the contact device. The specified range can thus be a range open at one end and also a range bounded at both ends.
[0022] The invention in certain embodiments has the advantage that all electrical components are preferably arranged on the main body, so that the contact device is free from electrical devices. Thus the production of the contact device is possible particularly economically, since only the contact area has to be shaped in conformity with the body parts of the animal, without in comparison to the prior art further pressure sensors and their wiring having to be provided on the contact device. In addition, in the injection device according to the present invention it is not necessary to make an electrical connection between the main body and the contact device, since in particular all electrical components are arranged on the main body. This also simplifies the production of the injection instrument.
[0023] A further advantage of certain embodiments is that the force measurement device makes it possible for a user of the injection device to simplify the injection. For only when the pressing force of the animal lies in the specified range is the injection administered. Since the pressing force is a measure of the fact that the animal has been correctly positioned in the contact area of the contact device, the injection takes place at the correct site. Thus with appropriate choice of the specified range, too light a pressing, which as a rule corresponds to unsatisfactory pressing of the animal on to the contact area, and/or too firm a pressing, which can result in deformations of the animal by the pressing and hence an unplaced injection, can be avoided.
[0024] The force measurement device can comprise a first force sensor and a second force sensor at a distance therefrom, wherein the control device can only activate the injection instrument if the difference between the force measured by the first force sensor and the second force sensor lies below a specified value. In particular, both force sensors can be positioned at a distance in a horizontal direction from a midline of the contact area. In particular, the support device comprises three support elements, wherein the first support element comprises the first force sensor and/or the second support element comprises the second force sensor.
[0025] The support elements can be configured as projections on which the contact device, with in particular correspondingly shaped recesses, can move in the pressure application direction. For example, the support elements are designed as rods, pillars or cylinders, while the contact device has a corresponding, in particular cylindrical, cavity, so that the contact device can be moved towards the main body in the pressure application direction. In particular, the axial orientation of the cavity and of the support elements corresponds to the pressure application direction. Alternatively, one or more support elements can lie against a contact surface of the contact device, wherein the contact surface is preferably bounded in the circumferential direction at least in certain areas by a side wall. The side walls serves in particular for the positioning of the contact device on the main body.
[0026] The first force sensor and the second force sensor, which can measure the pressing force, can be incorporated in a first support element and a second element respectively. Preferably the first support element and the second support element, and thus also the first force sensor and the second force sensor, are arranged in a horizontal direction on the main body, so that it is possible with the first and the second force sensor to determine a force difference in a horizontal direction. The horizontal direction is in particular perpendicular to the orientation of the animal in the contact area. For example, the first support element and the second support element are arranged left and right of a vertical midline. The midline can represent the axis of symmetry of the contact area, wherein the first force sensor and the second force sensor are arranged symmetrically to this midline. With the force sensors it is thus possible to determine a balance of the pressing force in the horizontal direction. Horizontal and vertical relate for example to the base on which the main body stands and thus also to a floor area of the stand device.
[0027] The first and/or the second force sensor can be configured to measure a force acting thereon. The force sensor can be designed as a spring force transducer or as a piezo force transducer. In particular, the first and/or the second force sensor are designed as weighing cells, as is known from the prior art. The first and the second force sensor are preferably identically designed. Depending on the type of the force sensor, the required movability of the contact device relative to the main body in the pressure application direction varies. With use of a weighing cell, the contact device only has to be moved slightly in the pressure application direction.
[0028] The force sensor can be disposed on an end of the respective support element facing the contact device. Depending on the design of the force sensor, the contact device is moved in the direction of the main body, and thus the force sensor compressed, by the pressing force. Alternatively, by pressing of the contact device onto the main body the force sensor changes in its extension only slightly, wherein the pressing force is detected at the same time.
[0029] The control device preferably only activates the injection instrument if the difference between the force measured by the first force sensor and the second force sensor lies below a specified value. For example, the control device does not activate the injection instrument until the total force of the pressing of the animal against the contact device exceeds a certain threshold value and/or at the same time the difference between the force measured by the first and the second force sensor lies below a certain limit value. It is thus ensured that the total pressing force lies above a threshold value, so that it can be assumed that the animal is lying correctly in the contact area, wherein a different pressing onto one side of the contact area is at the same time avoided. This represents a further indication that the animal has been correctly positioned on the contact device, so that the injection is administered at the intended site. Thus an advantage of the provision of two force sensors claimed is that it can be better determined that the animal is lying correctly against the contact device, in particular as regards the balance of force in the horizontal direction.
[0030] The injection device can comprise a capacitive sensor for detecting the presence of the animal at the contact area, wherein preferably the control device can only activate the injection instrument if the capacitive sensor detects the presence of the animal. In particular a third support element of the support device comprises the capacitive sensor.
[0031] The capacitive sensor can operate on the basis of the change in the capacity of a single condenser or a whole condenser system. For example, the capacitive sensor is such as is known from the prior art. In a preferred embodiment the capacitive sensor is provided at an end of the third support element facing the contact device, so that it is designed to detect the proximity or presence of an animal. In particular, the contact device in the vicinity of the third support element is designed such that the measurement of the capacitive sensor is not affected. This can for example be carried out by appropriate choice of the material of the contact area in the region of the third support element.
[0032] The capacitive sensor, in particular the third support element, is preferably positioned such that it is in the vicinity of an upper region of the contact area. In particular, the capacitive sensor is positioned such that with its aid it can be determined whether the animal is present in a peripheral region, in particular the upper peripheral region of the contact area. For example, the third support element is arranged displaced in a vertical direction relative to the first and/or second support element. Preferably the third support element and/or the capacitive sensor are positioned on the midline of the contact device.
[0033] Through the preferred arrangement of the capacitive sensor such that it corresponds to a peripheral region of the contact area, it can with its aid be determined whether the animal is correctly lying against a peripheral region of the contact area. In particular, the control device activates the injection instrument if the capacitive sensor detects the presence of the animal, the total force lies above a specified threshold value and/or the measured force difference between the first force sensor and the second force sensor lies below a certain limit value. The result of this is that the correct positioning on the contact device can be especially well determined, which results in an injection at the desired site.
[0034] The contact area can comprise a contact section and a pressure application area which is movable towards the contact section in the pressure application direction. The pressure application area can for example have a movement range in the direction of the pressure application direction of at most 1 mm, 2 mm, 3 mm, 4 mm, 5 mm or at most 10 mm.
[0035] The pressure application area corresponds in particular to a part of the animal for which it is especially important that it is lying against the contact device. For example, the pressure application area serves for the contact of the breastbone and a part of the breast muscle of a bird or poultry. The correct positioning of the breastbone is an important indication that the injection can be carried out at the correct site of the breast muscle.
[0036] The contact section and the pressure application area together form the contact area, so that the contact section is also shaped in conformity with the anatomy of the animal to be pressed on. In particular, the contact section surrounds the pressure application area. The contact section in particular together with the pressure application area forms an essentially continuous contact surface for the animal to be treated (apart from a small gap between the outer contact section and the inner pressure application area).
[0037] The relative movability of the pressure application area relative to the contact section makes it possible to determine the correct positioning of the animal at the pressure application area separately from the positioning of the animal at the contact section. In particular, the movability of the pressure application area relative to the contact section provides a further parameter by means of which the positioning of the animal against the contact device can be determined.
[0038] The movability of the pressure application area relative to the contact section is preferably free from initial tension. For example, the pressure application area is mounted with play at the contact section. The pressure application area is in particular moved from the contact section towards the main body by the pushing of the animal against the contact device.
[0039] The contact section and/or the pressure application area can be produced from plastic or metal. In particular, these are produced by injection molding, wherein other production methods, such as for example deep-drawing, are also possible.
[0040] The pressure application area can sit in a recess of the contact section.
[0041] The contact section can surround the recess completely, so that the pressure application area can be supported only on the contact section. In this way, it is possible to produce a relative movement of the pressure application area with respect to the contact section.
[0042] The pressure application area can be attached to the contact section by means of a snap connection. This is preferably designed such that the snap connection cannot be non-destructively separated. Alternatively, the snap connection can be non-destructively released. The snap connection can be produced as known from the prior art. The snap connection enables the movability of the pressure application area relative to the contact section in the pressure application direction. Preferably, snap connections are provided at three sites along the recess.
[0043] The pressure application area can include at least one projection or one slot, wherein the contact section comprises at least the other of the projection and the slot, wherein the projection and the slot are provided with play in the pressure application direction.
[0044] The pair of projection and slot represents an example of a snap connection. Preferably, three pairs of projections and slots are provided. The slot can be designed as a recess into which the projection engages. For example, the pressure application area has three projections which engage with play in the slots of the contact section. The play is provided in particular in the pressure application direction, so that the pressure application area can move freely in the pressure application direction relative to the contact section.
[0045] The pair of projection and slot can also be designed circumferential around the pressure application area. The provision of a movable connection by means of projection and slot has the advantage that for attachment the pressure application area can be clicked into the contact section.
[0046] The force measurement device can include a third force sensor arranged on the main body, wherein the third force sensor is preferably designed to measure the force acting on the pressure application area. In this case, the first and second force sensor can measure the forces of the contact section.
[0047] The third force sensor can be provided separately from the support elements of the support device. In a preferred embodiment, the third force sensor does not contribute to the support of the contact device on the main body. Rather it serves for the measurement of a force which acts on the pressure application area. Thus with the aid of the third force sensor in conjunction with the movable arrangement of the pressure application area on the contact area it is possible additionally to check whether the animal is correctly positioned at the pressure application area.
[0048] The third force sensor can be a force sensor similar to the first and/or second force sensor. The third force sensor is preferably arranged opposite the pressure application area.
[0049] The control device can be configured to only activate the injection instrument if the force measured by the third force sensor lies in a specified range. Preferably, the specified range is a force range bounded at both ends. It can therefore be established by means of the third force sensor that the force acting on the pressure application area is not too great and not too small, which indicates the correct positioning of the animal against the pressure application area.
[0050] The control device can be configured to only activate the injection instrument when the force measured by the first and the second force sensor lies above a certain threshold value, the difference between the force measured by the first force sensor and the second force sensor lies below a certain limit value, the capacitive sensor detects the presence of an animal and/or the force measured by the third force sensor lies within the specified force range. This criterion is particularly well suited to indicating the correct positioning of the animal against the contact device. In particular, the positioning of the animal against the contact device takes place in that firstly the force balance in the horizontal direction is determined by means of the first and second force sensor. Then the pressing force is increased so that the animal lies against the pressure application area with appropriate force.
[0051] The control device can also be configured to activate the injection instrument if one of the aforesaid conditions or any combination of these conditions is fulfilled.
[0052] If the force measurement does not fulfil the specified condition, the control device can cause the injection instrument to travel back immediately to its original, non-activated position. Alternatively, the control device can discontinue the injection depending on the progress of the injection if the force measurement and/or the capacity measurement indicates a no longer correct positioning of the animal. For example, even with an incorrect positioning of the animal the injection can be continued if almost the whole of the injection preparation has been injected into the animal.
[0053] The control device can also continue the injection to the end irrespective of whether the previously occupied correct positioning has been vacated, since the animal by movements temporarily causes a deviating force during the injection. For example, the injection is only discontinued if the deviation of the measured forces and/or the measurement of the capacity sensor deviates from the limit values by a specified amount.
[0054] The third force sensor preferably has a bar projecting perpendicular to the pressure application direction, whereby the pressure application area lies against the bar. The bar is preferably made elongated, in particular rectangular. The third force sensor preferably has a base part projecting from the main body in the pressure application direction from which the bar projects sideways. The bar serves in particular for the force transfer of the force acting on the pressure application area to the sensor of the third force sensor. For example, the sensor of the third force sensor is provided on the base part which is arranged offset with respect to the pressure application area. The pressure application area is preferably arranged opposite the injection instrument, so that no space is available on the main body for the attachment of the third force sensor. With the aid of the bar, the offset between base part and pressure application area can be bridged.
[0055] The contact area can include at least one opening for the passage of a needle (or optionally several needles) of the injection instrument (or of another discharge-side end of the injection instrument), with the opening preferably being arranged in the pressure application area.
[0056] The opening can be configured such that the injection instrument, in particular the needle thereof, can be introduced into the animal through the opening. For example, the opening is made elongated in a horizontal direction, so that even with an arrangement in which the needle is arranged inclined relative to the surface of the main body and/or the contact device, the needle can be passed through the opening.
[0057] Since the pressure application area represents a particularly important indicator of the correct positioning of the animal against the contact device, the pressure application area is in particular selected such that it is located at the site of the injection to be carried out, which is represented by the opening. When it is now determined by the third force sensor that the pressing force in the pressure application area is in the specified correct force range, it can be assumed that the injection takes place at the correct site on the animal.
[0058] Preferably, two openings are provided in the contact area, wherein each opening is assigned to one needle of the injection instrument. Both the openings are preferably arranged in a horizontal direction, in particular symmetrically to the midline of the contact device. It is however also possible to provide a single opening for both needles.
[0059] The injection instrument can be arranged on the main body such that in the non-activated state the needle does not project from the opening. In particular, the injection instrument can be positioned such that after the activation, that is after the operation of the actuator of the injection instrument, its needle protrudes through the opening from the contact area, so that it has been inserted into the animal. Thus the injection takes place through the movement of the needle of the injection instrument and not through a displacement of the contact device. The contact device is preferably mounted movable on the main body in such a manner that when the contact device has been moved completely towards the main body, the needle does not protrude into the opening if the injection instrument is not activated.
[0060] Certain embodiments include the advantage that the needle of the injection instrument does not protrude from the contact device, so that there is a low risk of injury (in particular of the persons who push the animals onto the contact area) by the needle of the injection instrument. The injection instrument only moves out from the opening when an animal is correctly positioned, so that there is then also no risk of injury to the user.
[0061] The injection device can include a display device on which information concerning the actual positioning of the animal against the contact area based on the measurements of the force measurement device is displayed. The display device can display whether the difference between the force measured by the first force sensor and the second force sensor lies below a specified value and/or whether the force measured by the third sensor lies in the specified range and/or whether the capacitive sensor detects the presence of the animal.
[0062] The display device gives the user a visual feedback as to whether the respective measured forces indicate a correct positioning of the animal against the contact device. For example, the user immediately sees whether the force difference lies below the defined limited value, and can thus maintain this positioning and adapt the positioning appropriately with respect to the capacitive sensor and the third force sensor in order also to fulfil the conditions specified there. Thus the correct positioning of the animal against the contact device is facilitated.
[0063] The display device preferably displays the difference between the force measured by the first force sensor and the second force sensor and/or the force measured by the third force sensor. For example, the difference between the force measured by the first force sensor and the second force sensor can be displayed by a bar which is elongated in its extent depending on the side of the force excess and its height. Alternatively, the difference can also be represented by a point which, depending on the difference between the force measured by the first force sensor and the second force sensor, moves away from a zero point at which the force measured by the first force sensor and the second force sensor is the same.
[0064] The force measured by the third force sensor can be displayed as a bar, wherein a region corresponding to a specified force range is displayed at the same time. Presence in the appropriate force range can for example be additionally emphasized by a changing bar color. The display device accordingly helps the user to implement the correct pressing force and hence the correct positioning of the animal against the contact device.
[0065] It is understood that the features named above and those yet to be explained below can be used not only in the stated combinations but also in other combinations or alone, without departing from the scope of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0066] FIG. 1 is a schematic perspective representation of one embodiment of the injection device according to the invention, wherein for better clarity of representation the contact device is shown detached from the main body.
[0067] FIG. 2 is a top view of a main body of the injection device according to FIG. 1 .
[0068] FIG. 3 is a top view of the front side of the contact device of the injection device according to FIG. 1 .
[0069] FIG. 4 is a top view of the rear side of the contact device of the injection device according to FIG. 1 .
[0070] FIG. 5 is an enlarged cross-section view of the contact device of the injection device according to FIG. 1 along the cut line V-V drawn onto FIG. 4 .
[0071] FIG. 6 is a top view of a display device of the injection device according to FIG. 1 .
[0072] While the invention is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be understood, however, that the intention is not to limit the invention to the particular example embodiments described. On the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the scope of the invention as defined by the appended claims.
DETAILED DESCRIPTION
[0073] In the following descriptions, the present invention will be explained with reference to various exemplary embodiments. Nevertheless, these embodiments are not intended to limit the present invention to any specific example, environment, application, or particular implementation described herein. Therefore, descriptions of these example embodiments are only provided for purpose of illustration rather than to limit the present invention.
[0074] In the embodiments represented in FIGS. 1 to 6 , the injection device 10 comprises a main body 12 , a contact device 14 , a support device 16 , a force measurement device 18 , a control device S and a display device 20 . The control device S is shown dotted in FIG. 1 , since it is positioned within the main body 12 .
[0075] The injection device 10 serves for administration of injections to an animal. In the embodiment shown, vaccines or medicaments for the treatment of diseases can be administered intramuscularly to a chicken by means of the injection device 10 .
[0076] The main body 12 has a housing 22 with a cover 24 attached thereon. The cover 24 can be removed from the housing 22 in order to access an injection instrument 26 arranged in the housing 22 .
[0077] As can be seen particularly clearly in FIG. 2 , the injection instrument 26 comprises two syringes 28 (e.g. self-filling syringes), which each have a needle 30 and an actuator. The actuator moves the needle 30 out from the housing 22 of the main body 12 when the control device S activates the injection instrument 26 . In addition, the injection instrument 26 can have a pump or refilling device, not shown, with which injection preparation can be pumped through the needle 30 or which after each injection fills the syringe 28 with the injection preparation for the next injection.
[0078] The contact device 14 is arranged movable relative to main body 12 on the basis of the support device 16 . In particular, the contact device 14 is assembled removable from the main body 12 . Thus different contact devices 14 can be successively attached to the main body 12 , with the different contact devices 14 being matched for example to the animal species or breed to be treated, the age of the animals and/or their size.
[0079] The contact device 14 has a shaped contact area 34 , which is shaped in conformity with the animal and in particular in conformity with the anatomy in the region of the desired injection site. In the embodiment described here, the contact area 34 is shaped in conformity with the breast region of a chicken. The contact area 34 is made in two parts and comprises an outer contact section 34 ′ and an inner pressure application area 36 . The outer contact section 34 ′ has a recess 36 ′, in which the pressure application area 36 is positioned such that the outer contact section 34 ′ together with the inner pressure application area 36 form an essentially continuous contact surface for the chicken to be inoculated (apart from a small gap between the outer contact section 34 ′ and the inner pressure application area 36 ). The pressure application area 36 is shaped in conformity with the size of a breastbone of the chicken and thereby helps to determine the correct positioning of the breastbone of the chicken against the contact device 14 , as is further described below. In the pressure application area 36 , two openings 38 are provided, as for example is clear from FIG. 3 . The openings 38 are positioned corresponding to the syringes 28 of the injection instrument 26 in a horizontal direction symmetrically to a midline M of the contact device 14 . After their activation by the control device S, the needles 30 of the syringes 28 move into the breast muscle of the chicken through the openings 38 .
[0080] The pressure application area 36 is arranged movable relative to the contact section 34 ′ in a pressure application direction D ( FIG. 1 ). For this, the pressure application area 36 has three separate projections 35 , which project on the rear side R of the contact section 34 ′ over the recess 36 ′ and are guided in three slots 37 , which are made on the rear side R. The slots 37 are made such that the pressure application area 36 is held and that a movement of the projections 35 and thus of the pressure application area 36 in the pressure application direction D is possible. The possible travel is 2 mm.
[0081] The support device 16 has three pillar-shaped support elements 40 a , 40 b , 40 c . As can be seen clearly in FIG. 2 , the support elements 40 a - 40 c have a cylindrical shape, so that the contact device 14 can be pushed onto the support elements 40 a - 40 c . For this, the contact device 14 has two cylindrical cavities 39 a and 39 b , shown in FIG. 4 , which are matched to the size of the support elements 40 a and 40 b . The length of the support elements 40 a and 40 b and the depth of the cavities 39 a and 39 b in the contact device 14 are selected such that at the maximum push-in depth of the contact device 14 this is at a distance from the main body 12 . The contact device 14 is lies against the third support element 40 c by means of a contact surface 41 .
[0082] In the representation of FIG. 1 , for better clarity the contact device 14 is shown, in the form of an exploded view, at a distance from the main body 12 . Naturally, during the operation of the injection device 10 the contact device 14 sits on the support elements 40 a , 40 b and 40 c and is guided by these such that the contact device 14 is movable along the pressure application direction D.
[0083] The first support element 40 a is positioned at a distance from the second support element 40 b in a horizontal direction, in particular symmetrically to the injection instrument 26 . On the axis of symmetry of the first support element 40 a and the second support element 40 b , the third support 40 c is arranged offset in a vertical direction which is perpendicular to the horizontal direction. The axis of symmetry coincides with a midline M of the contact device 14 .
[0084] The force measurement device 18 comprises three force sensors 42 a , 42 b and 42 c , which are each designed as a weighing cell known from the prior art. A first force sensor 42 a is built into the first support element 40 a , while a second force sensor 42 b is positioned in the second support element 40 b.
[0085] A third force sensor 42 c is positioned on the midline M. The third force sensor 42 c has a base part 43 and a bridge or bar 44 . The bridge 44 extends up to the openings 38 , while its free end lies somewhat below the openings 38 . The bridge 44 is provided since, because of the anatomy of the chicken and in particular the breastbone, for which the pressure application area 36 is provided, the section projecting the furthest in the direction of the main body 12 lies in the region of the two openings 38 . In this region, because of the two syringes 28 , there is not sufficient space in the main body 12 for the third force sensor 42 c . The bridge 44 is therefore provided for force transfer from the pressure application area 36 to the third force sensor 42 c . As can be seen from FIG. 5 , the pressure application area 36 has a projecting contact section 44 ′, which during the operation of the injection device presses against the bridge 44 at the free end of the bridge 44 .
[0086] The injection device 10 further has a capacitive sensor 46 , which is positioned at the end of the third support element 40 c facing the contact device 14 . The capacitive sensor 46 detects the presence of an animal in its vicinity. For this, in the region adjacent to the capacitive sensor 46 the contact device 14 is designed in such a manner that it does not interfere with the capacity measurement of the capacitive sensor 46 . By means of the capacitive sensor 46 , it can be determined whether the animal is positioned in an upper peripheral region of the contact area 34 .
[0087] As can be seen in FIG. 6 , the display device 20 shown enlarged in FIG. 6 has a display 50 for the force measured by means of the third force sensor 42 c , a display 52 for the difference of the force measured by means of the first force sensor 42 a and the second force sensor 42 b and a display 54 for the capacitive sensor 46 .
[0088] The display 50 shows the force measured by means of the force sensor 42 c in the form of a point the vertical positioning whereof indicates the magnitude of the force. The display 50 further has markings which correspond to the specified force range. In the embodiment shown, the point is located in the specified force range, so that the force applied to the pressure application area 36 lies in the specified range.
[0089] In the case of the display 52 , it is shown by means of the position of a point whether the force applied to the first force sensor 42 a or to the second force sensor 42 b is greater than the force applied to the respective other force sensors. In the embodiment shown, the point is located in the middle of the display 52 , which indicates that the force applied to the first force sensor 42 a or to the second force sensor 42 b is of equal magnitude. The display 54 is designed as a lamp, wherein the illumination of the display 54 indicates that the capacitive sensor 56 has detected the presence of the animal.
[0090] The mode of functioning of the injection device 10 is explained below:
[0000] A user of the injection device 10 holds an animal against the contact device 14 . By correct positioning of the animal against the contact area 34 , that is by application of the appropriate pressing force, the control device S triggers an injection. For this, the force difference between the force measured by the first force sensor 42 a and the second force sensor 42 b must lie below a certain limit value, that is, the force balance in the horizontal direction must be present. This indicates that the animal is not being pushed on obliquely. If the force balance is present and a force in the specified range is present on the third force sensor 42 c , the control device S activates the injection instrument 26 and the injection is performed, if further the presence of the animal is detected by means of the capacitive sensor 46 .
[0091] While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiments, it will be apparent to those of ordinary skill in the art that the invention is not to be limited to the disclosed embodiments. It will be readily apparent to those of ordinary skill in the art that many modifications and equivalent arrangements can be made thereof without departing from the spirit and scope of the present disclosure, such scope to be accorded the broadest interpretation of the appended claims so as to encompass all equivalent structures and products. Moreover, features or aspects of various example embodiments may be mixed and matched (even if such combination is not explicitly described herein) without departing from the scope of the invention.
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An injection device for administration of an injection to an animal can include a main body, which contains an injection instrument, a contact device, which has a contact area which is shaped in conformity with a body part of the animal to which the injection is to be administered. A support device which supports the contact device on the main body can be movable in a pressure application direction. A force measurement device including at least one force sensor can be designed to measure at last one force with which the contact device acts on the main body. A control device can activate the injection instrument if the force measured by the force measurement device lies in a specified range.
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This application is a continuation-in-part of Ser. No. 960,987 filed Nov. 15, 1978, now U.S. Pat. No. 4,231,783.
This invention relates to novel 2-imino-1,3-dithio and 1,3-oxathio heterocycles and derivatives thereof as well as their use in compositions and methods for reducing herbicidal injury. More specifically, the invention relates to novel compositions and methods for reducing injury to crop plants by herbicides such as thiocarbamates and acetanilides, which comprises treating the crop plant locus or the seed of the crop plant with an effective amount of compounds which will be described more fully below.
BACKGROUND OF THE INVENTION
Herbicides are widely used to control weed growth in growing crop plants. Unchecked weed growth is detrimental to the crop plant because weeds compete with crop plants for light, water and various nutrients. This can result in lower crop yields as well as poorer crop quality. The presence of weeds in a growing crop also interferes with the cultivation and harvesting of the crop plant. Among the commercially available herbicides, thiocarbamates and acetanilides have proven to be effective in controlling various weed pests. Unfortunately, thiocarbamate and acetanilide herbicides can also cause serious injury to some crop plants at application rates necessary to stunt or kill weeds. A compound or composition which protects the crop plant from the action of the herbicide, without reducing the herbicidal effectiveness against the weed to be controlled, would be beneficial.
Compounds which are useful in reducing or eliminating crop injury are variously referred to by those skilled in the art as antidotes, safeners or antagonistic agents. It has been found that certain 2-imino derivatives of 1,3-dithiolane, 1,3-dithiole, 1,3-dithiane, 1,3-dithietane and 1,3-oxathiole are effective safening agents. Certain of these compounds are known in the art; the following patents are representative of the art in this area.
U.S. Pat. No. 3,449,365 discloses 2-imino-4-alkalidene-1,3-dithiolanes and teaches that said compounds are useful as insecticides, acaricides and nematocides. U.S. Pat. No. 3,449,366 discloses 2-amino-4,5-substituted-1,3-dithioles which are useful as insecticides. U.S. Pat. No. 3,389,148 discloses processes for preparing substituted 1,3-dithioles, 1,3-dithianes, 1,3-dithiolanes and the salts thereof which are intermediates in the preparation of phosphorylated imino compounds. U.S. Pat. No. 3,189,429 and 3,139,439 disclose the preparation and herbicidal use of the halide salts of 2-dialkylamino-1,3-dithiolane derivatives. British Pat. No. 1,367,862 discloses substituted phenyl-2-imino-1,3-dithietanes which are chemosterilants of adult female Ixodides. U.S. Pat. No. 4,025,532 discloses 2-(o-tolyl)imino-1,3-dithioles which are ixodicides. None of the above patents teach or suggest that the substituted 2-imino-1,3-dithio and 1,3-oxathio heterocyclic compounds of the present invention would be useful as herbicidal antidotes.
DESCRIPTION OF THE INVENTION
It has been found that various crop plants can be protected against the herbicidal action of thiocarbamate and acetanilide herbicides, without a corresponding reduction in injury to the weeds, by the application to the crop plant locus or the seed of the crop plant prior to planting of an effective safening amount of a compound having the formula
R-N=A
or an agriculturally acceptable acid addition salt thereof, wherein R is hydrogen, lower alkyl, or ##STR1## R 1 is hydrogen or lower alkyl; X and Y independently equal hydrogen, lower alkyl, lower alkoxy or halogen; n is 0, 1, 2 or 3; A is ##STR2## R 2 is hydrogen or methyl; R 3 is hydrogen or halogen; R 4 is hydrogen, methyl or phenyl; Z is oxygen or sulfur; provided that when n is 1 and A is ##STR3## R 1 cannot equal ethyl and when n is 1 and A is ##STR4## R 1 cannot equal n-propyl or isobutyl.
It is believed that compounds described by the above formula are novel except where R equals hydrogen, where A equals ##STR5## and n equals 0.
Preferred compounds employed in the invention are those in which R is ##STR6## Among the above-described preferred compounds, the most preferred are those in which R 1 is methyl and X and Y are hydrogen.
As used herein the term "lower alkyl" includes those members including straight and branched chain, having from 1 to 5 carbon atoms inclusive, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and the like. The term "lower alkoxy" includes straight and branched chain members having from 1 to 5 carbon atoms, inclusive, for example, methoxy, ethoxy, isopropoxy and the like. The term "halogen" or "halo+ is understood to include chlorine, bromine, fluorine and iodine atoms, preferably chlorine.
The agriculturally acceptable acid addition salts of the compounds of the foregoing formula are derived from "strong acids" which is understood herein to mean those inorganic and organic acids having a dissociation constant equal to or greater than about 5×10 -2 , for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, tri-halogenated acetic acid, oxalic acid and the like. Preferred salts are those derived from the hydrohalic acids, especially hydrochloric acid.
"Antidote", "safener" or "antagonistic agent" when used herein, refer to compounds which counteract the herbicidal action of a herbicide on a crop plant thereby reducing or eliminating injury to the crop plant without reducing the effectiveness of the herbicide against the weed(s) to be controlled.
The "antidotes" of the present invention are particularly advantageous for cereal crop plants of the grass family (Gramineae), for example, oats, wheat, barley, rye, corn, rice and sorghum, preferably rice, sorghum and wheat.
Exemplary of the thiocarbamate herbicides useful herein is S-(2,3,3-trichloroallyl) diisopropylthiocarbamate, S-(2,3-dichloroallyl) diisopropylthiocarbamate, S-ethyl diisopropylthiocarbamate, S-propyl dipropylthiocarbamate and the like. The antidotes of the present invention are preferentially employed as safeners for S-(2,3,3-trichloroallyl) diisopropylthiocarbamate, commonly known as triallate.
Exemplary of the acetanilide herbicides is 2-chloro-2',6'-diethyl-N-(methoxymethyl) acetanilide, commonly known as alachlor, 2-chloro-2',6'-diethyl-N-(butoxymethyl) acetanilide, commonly known as butachlor, 2-chloro-N-isopropylacetanilide, commonly known as propachlor, and the like. Among the acetanilide herbicides, the antidotes of the present invention are preferentially employed as safening agents for alachlor and butachlor.
The amount of safening agent employed in the methods and compositions of the invention will vary depending upon the particular herbicide with which the agent is employed, the rate of application of the herbicide, the crop to be protected as well as the manner of application of the safening agent. In each instance, the amount employed is a safening effective amount, i.e., the amount which reduces crop injury by thiocarbamate or acetanilide herbicides.
The safening agent may be applied to the plant locus in a mixture with the herbicide, sequentially, or it may be applied directly to the seed of the crop plant. By application to the "plant locus" is meant application to the plant growing medium, such as the soil, as well as the seeds, emerging seedlings, roots, stems, leaves, flowers, fruits or other plant parts.
The amount of herbicide employed is well within the skill of the art and is disclosed in various patents. Alachlor and butachlor and their herbicidal use is disclosed in U.S. Pat. Nos. 3,442,945 and 3,547,620. Propachlor and its herbicidal use is disclosed in U.S. Pat. No. 2,863,752 and Re. 26,961. Triallate and diallate and their herbicidal use are disclosed in U.S. Pat. Nos. 3,330,643 and 3,330,821. Additionally, as is well known by those skilled in the art, the labels of commercially available thiocarbamate and acetanilide herbicides contain a complete description of the amount of herbicide to be employed to control the desired weed(s).
PREPARATION OF THE COMPOUNDS OF THE INVENTION
The substituted 2-imino-1,3-dithio- and oxathioheterocycles of the present invention are sulfur containing heterocycles generally known in the art as 1,3-dithiolanes, 1,3-dithioles, 1,3-dithianes, 1,3-oxathioles and 1,3-dithietanes.
The 1,3-dithiolanes of the invention are prepared according to several methods. The substituted 2-imino-4-dichloromethylene-1,3-dithiolanes may be prepared by cyclizing the appropriate 2,3,3-trihaloallyl N-substituted dithiocarbamate in the presence of a suitable solvent, for example, carbon tetrachloride, chloroform or toluene. When 2,3,3-trichloroallyl N-substituted dithiocarbamate is used, the reaction may be graphically illustrated as: ##STR7## Substituted 2-imino-4-methylene-1,3-dithiolanes may be prepared by reacting an amine, such as α-methylbenzylamine with an alkynyl halide containing 3 or 4 carbon atoms. The reaction may be graphically illustrated as ##STR8## These compounds may also be prepared by reacting approximately equimolar quantities of a substituted 2-propynyl dithiocarbamate with a non-oxidizing strong acid, such as hydrochloric. The overall reaction may be graphically written as: ##STR9##
The substituted 2-imino-4-methyl-1,3-dithioles may be prepared by reacting chloroallyl N-substituted dithiocarbamate with a non-oxidizing strong acid, such as hydrochloric or hydroiodic, etc. The reaction may be carried out in an inert inorganic or organic medium such as water, alcohol or a mixture of the same. It is generally preferably to employ an excess of acid.
The reaction may be illustrated as follows: ##STR10##
The substituted 2-imino-1,3-oxathioles of the invention may be prepared by reacting approximately equimolar portions of 1-substituted-3,3-dimethylthiourea and an appropriate halogenated aldehyde or ketone in an inert solvent such as dioxane, acetone, tetrahydrofuran and the like.
The reaction may be illustrated as: ##STR11##
The substituted 2-imino-1,3-dithianes of the invention may be prepared according to the following general reaction: ##STR12##
The preparation of the 1,3-dithietanes of the invention was carried out according to procedures known to those skilled in the art and described in U.S. Pat. Nos. 3,842,096, 3,928,382 and 3,954,801, herein incorporated by reference.
It will be recognized that the agriculturally acceptable salt of the above-described compounds is easily neutralized to form the free bases by the addition of a sufficient neutralizing amount of organic or inorganic base; contemplated, for example, are sodium hydroxide, potassium hydroxide, lithium bicarbonate, sodium bicarbonate, triethyl amine and sodium acetate.
To facilitate a further understanding of the present invention, the following illustrative examples are presented which are not to be taken as limitative of the invention.
EXAMPLE 1
2,3,3-Trichloroallyl N-(α-methylbenzyl) dithio carbamate
A two-phase mixture containing 6.0 g (0.0495 mol) dl-α-methylbenzylamine and 8.0 g (0.05 mol) 25% NaOH in 50 ml water was stirred rapidly at 0°-10° C. while 4.0 g (0.05 mol) carbon disulfide was added dropwise over 2-3 minutes. The mixture was stirred and allowed to warm to 20° C. over a one hour period. To this stirred slurry was added 9.0 g (0.05 mol) 1,1,2,3-tetrachloropropene in one portion. A yellow two phase mixture resulted and the temperature slowly rose to a maximum of 28° C. The mixture was heated gently to 45°-50° C. for three hours, then let cool and extracted with 300 ml ethyl ether. The ether solution was washed with two, 50 ml portions of water, treated with activated charcoal and MgSO 4 , filtered through Hy-flo and evaporated in vacuo below 40°/<1 torr to give 14.9 g (88%) of a light orange oil.
Anal. Calc'd for C 12 H 12 Cl 3 NS 2 : N, 4.11; Cl, 31.2; S, 18.8. Found: N, 4.26; Cl, 31.4; S, 18.8.
EXAMPLE 2
Benzylamine, N-[4-(dichloromethylene)-1,3-dithiolan-2-ylidene] Hydrochloride
A solution containing 16.35 g (0.05 mol) of 2,3,3-trichloroallyl N-benzyldithiocarbamate in 50 ml of carbon tetrachloride was placed in a photochemical reaction vessel fitted with a fritted disc bottom for sparging N 2 through the solution. A 450-watt, Hanovia high pressure mercury lamp, with a Pyrex filter, was inserted into the water-cooled quartz immersion well. The solution was agitated with a gentle stream of N 2 bubbles and photolyzed for 35 minutes. The CCl 4 was decanted off leaving a solid which was triturated with benzene, collected by filtration and air dried to give 7.2 g mp 158°-161° C. A sample was recrystallized from CHCl 3 /CCl 4 to give off-white crystals, mp 152°-159° C., yield 44%.
Anal. Calc'd for C 11 H 9 Cl 2 NS 2 .HCl: N, 4.29; Cl, 32.6; S, 19.6; N.E., 327. Found: N, 4.32; Cl, 32.4; S, 19.8; N.E., 321.
EXAMPLE 3
Benzylamine-,α-methyl-N-[(4-(dichloromethylene)-1,3-dithiolan-2-ylidene] Hydrochloride
This compound was prepared according to the procedure described in Example 2 except that 2,3,3-trichloroallyl-N-α-methylbenzyl dithiocarbamate was used. A solid was obtained in 47.5% yield, mp 152°-153° C.
Anal. Calc'd for C 12 H 11 Cl 2 NS 2 .HCl: N, 4.11; Cl, 31.2; S, 18.8 Found: N, 4.06; Cl, 31.3; S, 19.0
EXAMPLE 4
Benzylamine-,α-methyl-N-[4-(dichloromethylene)-1,3-dithiolan-2-ylidene]
A slurry consisting of 4.8 g (0.014 mol) of the hydrochloride salt of Example 3, in 60 ml of water was stirred and made slightly basic with triethylamine. The mixture was extracted with 50 ml ethyl ether. The separated ether solution was washed with 2, 25 ml portions of cold water, dried over MgSO 4 and evaporated in vacuo at 50°/<0.5 torr to give 4.1 g light amber oil. The oil which solidified on standing at room temperature was recrystallized from pet ether, mp 39°-40.5° C., yield 99%.
Anal. Calc'd for C 12 H 11 Cl 2 NS 2 : N, 4.60; Cl, 23.3; S, 21.1. Found: N, 4.71; Cl, 23.3; S, 21.1.
EXAMPLE 5
Benzylamine, α-isopropyl N-[4-(dichloromethylene)-1,3-dithiolan-2-ylidene]
A solution of 35.6 g (0.097 mol) 2,3,3-trichloroallyl N-(α-isopropyl) benzyldithiocarbamate in 100 ml chloroform was photolyzed for 21/2-3 hours. After evaporation of the chloroform the residue was treated with benzene but no crystalline hydrochloride salt formed. The benzene solution was diluted with ethyl ether and the organic solution treated with dilute NaOH. The organic layer was then dried and evaporated to give 29.3 g red amber oil. A 10 g portion of this oil was purified by HPLC (High performance liquid chromatography) on silica gel using toluene to give 5.0 g of the pure free base, yield 45.7%.
Anal. Calc'd for C 14 H 15 Cl 2 NS 2 : N, 4.21; Cl, 21.3; S, 19.3. Found: N, 4.16; Cl, 21.4; S, 19.4.
EXAMPLE 6
Isopropylamine, N-[4-(dichloromethylene) 1,3-dithiolan-2-ylidene] Hydrochloride
A solution containing 10.0 g (0.036 mol) 2,3,3-trichloroallyl N-isopropyldithiocarbamate in 100 ml CCl 4 was photolyzed for 0.5 hour. The solid product was collected by filtration and air dried to give 3.8 g, mp 149°-154° C. Crystallization from CHCl 3 /CCl 4 gave 2.5 g, mp 155°-157° C., yield 38%.
Anal. Calc'd for C 7 H 9 Cl 2 NS 2 .HCl: N, 5.03; Cl, 38.2; S, 23.0. Found: N, 5.05; Cl, 37.8; S, 22.8.
EXAMPLE 7
1,3-Dithiolane-,2-imino-4-dichloromethylene Hydrochloride.
A solution containing 4.8 g (0.02 mol) 2,3,3-trichloroallyl dithiocarbamate in 75 mls of chloroform was photolyzed for one hour. The chloroform was drawn off through the bottom sintered glass frit and the solid residue triturated with fresh chloroform then air dried to give 3.3 g, mp 180° C. (dec.)sinters at 120° C. Crystallization from MeOH/ethyl ether gave a light tan powder, mp 187° C.(dec.).
Anal. Calc'd for C 4 H 3 Cl 2 NS 2 .HCl: N, 5.92; Cl, 45.0; S, 27.1. Found: N, 5.94; Cl, 44.2; S, 26.7.
Following the procedures described in Examples 2-7, other N-(4-dichloromethylene)-1,3-dithiolanes of the invention were prepared. Table I describes these compounds in greater detail.
TABLE I__________________________________________________________________________ ##STR13##Example AnalysisNo. Empirical R Calc'd Found Solvent Mp °C. % Yield__________________________________________________________________________ 8 C.sub.5 H.sub.5 Cl.sub.2 NS.sub.2.HCl CH.sub.3 N, 5.59; 5.56 CCl.sub.4 193-194 46 Cl, 42.4; 42.6 S, 25.6; 25.7 9 C.sub.12 H.sub.10 Cl.sub.3 NS.sub.2.HCl ##STR14## N, 3.73; Cl37.8; S, 17.1; 3.78 37.7 17.1 CCl.sub.4 144-149 28.510 C.sub.13 H.sub.13 Cl.sub.2 NS.sub.2.HCl ##STR15## N, 3.95; Cl, 30.0; S, 18.1; 3.89 30.0 18.1 CHCl.sub.3 152.5-155.0 4311 C.sub.16 H.sub.19 Cl.sub.2 NOS.sub.2.HCl ##STR16## N, 3.39; Cl, 25,8; S, 15.5; 3.36 25.8 15.5 CHCl.sub.3 147-152.5 29.512 C.sub.13 H.sub.13 Cl.sub.2 NS.sub.2 ##STR17## N, 4.40; Cl, 22.3; S, 20.1; 4.43 22.4 20.1 CHCl.sub.3 Oil 94 13* C.sub.16 H.sub.19 Cl.sub.2 NS.sub.2 ##STR18## N, 3.89; Cl, 19.7 S, 17.8; 3.80 19.6 17.7 CHCl.sub.3 Oil 62__________________________________________________________________________ *Isolated by HPLC.
EXAMPLE 14
(After U.S. Pat. No. 3,449,365)
1,3-Dithiolan-2-imino-4-methylene-,Hydrochloride.
To a flask immersed in an ice-water bath was added 14.7 g (0.12 mol) 2-propynyl dithiocarbamate and the solid then mixed with 14 ml concentrated hydrochloric acid. The initial solid mass was stirred with a thermometer and the mass slowly liquified whereupon the reaction became extremely exothermic and the temperature rose to 90° C. in spite of the ice-bath cooling. When the reaction had subsided and the temperature of the mixture had cooled to 25°-30° C., the reaction mass was poured into 250 ml acetone. Upon cooling and scratching, a sandy solid formed which was collected by a filtration, washed with fresh acetone and air dried to give 14.4 g, mp 119°-122° C. Recrystallization from Methanol/ether gave sandy crystals, mp 122°-123° C.
EXAMPLE 15
Benzylamine-α-methyl-N-[4-(methylene)-1,3-dithiolan-2-ylidene.
A slurry consisting of 18.2 g (0.15 mol) of dl-α-methylbenzylamine and 100 ml water containing 23.2 g (0.15 mol) 25.8% NaOH was stirred at 0°-10° C. while 11.4 g (0.15 mol) carbon disulfide was added over 10 minutes. The pink solution was stirred and slowly warmed to 25° C. over one hour whereupon 17.8 g (0.15 mol) propargyl bromide was added in one portion. An exothermic reaction caused the temperature to rise to 35° C. and a yellow oil precipitated. The mixture was stirred and heated to 50°-55° C. for five hours then cooled to 25° C. with stirring, overnight. The oil was extracted with 300 ml of ethyl ether and the separated ether solution washed with 100 water, dried over MgSO 4 and evaporated in vacuo to give 34.2 g red-orange oil. The nmr spectrum indicated a mixture of the propargyl ester and the cyclic 1,3-dithiolane. The oil was heated in vacuo at 70°-80° C. to complete the cyclization. The oil was dissolved in 300 ml ethyl ether and the ether solution extracted with three, 100 ml portions of 10% HCl, followed by two, 50 ml portions of water. The combined acid extract was extracted twice with 50 ml ether, then carefully neutralized with 10% NaOH and the precipitated oil taken up in ether. The ether solution was dried and evaporated to 55°/<1 torr to give 19.5 g (86.5%) light yellow oil, n D 25 =1.6275.
Anal. Calc'd for C 12 H 13 NS 2 : C, 61.2; H, 5.57; N, 5.95; S, 27.2 Found: C, 61.5; H, 5.72; N, 6.04; S, 27.0
EXAMPLE 16
Benzylamine,α-methyl, 2,5-dimethoxy-N-[4-(methylene)1,3-dithiolan-2-ylidene].
A mixture of 10.0 g (0.034 mol) 2-propynyl N-[2,4-(dimethoxy)-α-methylbenzyl] dithiocarbamate and 30 ml conc. HCl was heated gently on a steam bath. After 10 minutes the solid carbamate had dissolved and the solution was heated an additional 10 minutes, cooled and ethyl ether added. The acid layer was separated, placed in an ice bath and carefully neutralized with 50% NaOH. The precipitated oil was extracted into ethyl ether and washed free of base with water, dried over MgSO 4 and evaporated in vacuo to give 9.7 g (97%) of a light amber oil, n D 25 1.6136.
Anal. Calc'd for C 14 H 17 NO 2 S 2 : C, 56.9; H, 5.80; N, 4.74; S, 21.7. Found: C, 57.1; H, 5.87; N, 4.70; S, 21.5.
EXAMPLE 17
Benzylamine-,α-methyl-N-[4-(methylene)-5-(methyl)-1,3-dithiolan-2-ylidene].
To a stirred solution containing 4.0 g (0.1 mol) NaOH and 10 ml of water in 100 ml dimethyl formamide there was added 2.1 g (0.1 mol) dl-α-methylbenzylamine at 20° C. followed by 7.6 g (0.1 mol) carbon disulfide over 5 minutes. After stirring for 15 minutes at 20°-25° C., 8.8 g (0.1 mol) of 3-chloro-1-butyne was added in portions. The resulting slurry was stirred at 20°-25° C. for one hour then heated gently to 30°-35° C. and stirred overnight at ambient temperature. The mixture was diluted with 400 ml cold water and extracted with 100 ml ethylene dichloride. The organic extract was washed with 50 ml water, dried over MgSO 4 and evaporated in vacuo below 30° C. to give 27.8 g orange oil which contained DMF. The oil was washed with water by decantation to remove DMF, then azeotroped with ethanol/benzene to give a crude oil which was dissolved in 300 ml ether and the solution extracted with 3 M HCl. The HCl extract was carefully nuetralized with 25% NaOH and the precipitated oil extracted into ether, the solution dried and evaporated at 50°/<0.5 torr to give 9.0 g clear amber oil, yield 36% n D 25 1.6620.
Anal. Calc'd for C 12 H 15 NS 2 : C, 62.6; H, 6.06; S, 25.7. Found: C, 62.7; H, 6.07; S, 25.6.
EXAMPLE 18
Benzeneethanamine, N-(4-methylene-1,3-dithiolan-2-ylidene)
A slurry containing 12.1 g (0.1 mol) β-phenethylamine and 15.4 g 25% sodium hydroxide in 100 ml water was stirred at 0°-10° C. while 7.7 g (0.1 mol) carbon disulfide was added dropwise. The orange solution was stirred rapidly and allowed to warm to room temperature over˜one hour. Propargyl bromide, 13.4 g (0.113 mol) was then added slowly at 20°-25° C. (ice bath cooling) and the resulting slurry was stirred at room temperature overnight. The oily product was extracted into 50 ml of ethyl ether, the ether solution dried over MgSO 4 and evaporated in vacuo to give 21.6 g of an orange liquid. A 10 g sample of the crude oil was purified by HPLC on silica gel using toluene as eluant to yield 4.1 g (32%) n D 25 1.6020.
Anal. Calc'd for C 12 H 13 NS 2 : C, 61.2; H, 5.57; N, 5.95; S, 27.3. Found: C, 61.1; H, 5.60; N, 5.92; S, 27.1.
EXAMPLE 19
Benzenepropaneamine, N-(4-methylene-1,3-dithiolan-2-ylidene)
A slurry containing 13.52 g (0.1 mol) of 3-phenyl-1-propylamine, 15.4 g (0.1 mol) 25% NaOH in 100 ml water was stirred vigorously at 0°-10° C. while 7.7 g (0.1 mol) carbon disulfide was added dropwise. The resulting solution was allowed to warm to˜25° C. over one hour whereupon 13.4 g (0.113 mol) propargyl bromide was added slowly at 20°-25° C. with ice bath cooling. The resulting two-phase mixture was stirred overnight then extracted with 50 ml ether. The ether solution was separated, washed until neutral with water, dried over MgSO 4 and evaporated in vacuo to give 22.7 g amber oil. After standing at room temperature for 8 days, 10 g of the crude oil was purified by HPLC on silica gel using toluene as eluant. Recovered 1.4 g (13%) of the pure 2-(3-phenyl-1-propyl)imino-4-methylene-1,3-dithiolane, n D 25 1.5983.
Anal. Calc'd for C 13 H 15 NS 2 : C, 62.6; H, 6.06; N, 5.62; S, 25.7. Found: C, 62.4; H, 6.09; N, 5.58; S, 25.7.
The procedures of Examples 13-19 were used to prepare other N-(4-methylene)-1,3-dithiolanes which are described in Table II.
TABLE II__________________________________________________________________________ ##STR19##Example No. Empirical R Calc'd Found n.sub.D.sup.25° % Yield__________________________________________________________________________20 C.sub.11 H.sub.11 NS.sub.2 ##STR20## C, 59.7; H, 5.01; N, 6.33; S, 29.0; 59.7 4.97 6.24 29.2 1.6489 6621 C.sub.7 H.sub.11 NS.sub.2 (CH.sub.3).sub.2 CH N, 8.08; 7.88 1.6041 88.5 S, 37.0; 36.822 C.sub.13 H.sub.15 NS.sub.2 ##STR21## C, 62.6; H, 6.06; N, 5.62; S, 25.7; 62.7 6.09 5.59 25.7 1.6175 4323 C.sub.14 H.sub.17 NS.sub.2 ##STR22## C, 63.9; H, 6.51; N, 5.32; S, 24.4; 64.0 6.58 5.19 23.9 1.6083 6024 C.sub.14 H.sub.17 NS.sub.2 ##STR23## C, 63.9; H, 6.51; N, 5.32; S, 24.4; 64.2 6.61 5.20 23.7 1.6110 1925 C.sub.16 H.sub.21 NOS.sub.2 ##STR24## C, 62.5; H, 6.88 N, 4.56; S, 20.9; 63.2 6.96 4.71 20.2 1.5875 1126* C.sub.16 H.sub.21 NS.sub.2 ##STR25## C, 65.9; H, 7.26; N, 4.80; S, 22.0; 66.3 7.23 4.70 21.6 1.5856 5527* C.sub.14 H.sub.17 NS.sub.2 ##STR26## C, 63.9; H, 6.51; N, 5.32; S, 24.4; 63.8 6.52 5.40 24.3 1.5902 3728* C.sub.12 H.sub.12 ClNS.sub.2 ##STR27## C, 53.4; H, 4.48; Cl, 13.1; S, 53.5 4.53 13.2 23.6 1.6154 2729* C.sub.14 H.sub.17 NS.sub.2 ##STR28## C, 63.9; H, 6.51; N, 5.32; S, 24.4; 63.7 6.58 5.28 24.3 1.6177 2830* C.sub.13 H.sub.15 NS.sub.2 ##STR29## C, 62.6; H, 6.06; N, 5.62; S, 25.7; 62.4 6.06 5.56 25.6 1.5992 1431* C.sub.15 H.sub.19 NS.sub.2 ##STR30## C, 64.9; H, 6.90; N, 5.05; S, 23.1 64.8 6.88 5.02 23.0 1.5828 3232* C.sub.15 H.sub.19 NS.sub.2 ##STR31## C, 64.9; H, 6.90; N, 5.05; S, 23.1; 64.8 6.96 4.98 23.0 1.5960 3233* C.sub.11 H.sub.10 ClNS.sub.2 ##STR32## C, 51.6; H, 3.94; N, 5.48; Cl, 13.9; S, 51.7 3.98 5.47 13.8 25.0 1.6413 334* C.sub.11 H.sub.10 ClNS.sub.2 ##STR33## C, 51.6; H, 3.94; N, 5.48; S, 25.1; 51.4 3.99 5.46 25.0 1.6475 22__________________________________________________________________________ *Isolated by HPLC.
EXAMPLE 35
(After U.S. Pat. No. 3,449,366)
1,3-Dithiol-2-imino,4-methyl-,Hydrochloride
A mixture of 4.5 g (0.027 mol) 2-imino-4-methylene 1,3-dithiolane hydrochloride, Example 14, in 9 ml concentrated hydrochloric acid was heated at reflux in an oil bath (100°-110°) for three hours then allowed to cool and stand overnight at 25°-30° C. The dark solution was decanted away from a dark amorphous solid into 150 ml dry acetone. The light brown lustrous crystals which formed on standing in the cold were collected by a filtrate ion, washed with fresh acetone and air dried to give 3.5 g, mp 170°-173° C. Recrystallization from methanol gave bright yellow crystals which quickly darkened on air drying, mp 168°-170° C.
EXAMPLE 36
Benzylamine-,α-methyl-N-[4-(methyl)-1,3-dithiol-2-ylidene] Hydrochloride.
A mixture containing 10.0 g (0.037 mol) 2-chloroallyl N-(α-methylbenzyl) dithiocarbamate, 14 ml conc. HCl and 25 ml ethanol was stirred and heated under reflux for 4 hours. The dark mixture was allowed to cool to 25° C. and poured into 200 ml acetone. Since no crystals formed on chilling, the solvent was evaporated in vacuo and the residue treated with 150 ml benzene and re-evaporated at 50°/<0.5 torr to give 10.4 g light yellow semi-solid which crystallized on treating with 100 ml ethyl ether and 5 ml methanol to yield 6.3 g cream solid, mp 139°-150° C. A sample was recrystallized from ether/methanol to give colorless crystals, mp 165°-166° C., yield 34%.
Anal. Calc'd for C 12 H 13 NS 2 .HCl: N, 5.15; Cl, 13.0; S, 23.6, N.E. 272. Found: N, 5.27; Cl, 13.1; S, 23.7; N.E. 260.
EXAMPLE 37
Benzylamine-,α-t-butyl-p-methoxy-N-[4-(methyl)-1,3-dithiol-2-ylidene] Hydrochloride
A mixture containing 24 g (0.07 mol) 2-chloroallyl N-[α-t-butyl-o-methoxybenzyl] dithiocarbamate and 40 ml conc. HCl in 70 ml ethanol was heated under reflux for 3 hours. The mixture was treated with 300 ml chloroform and the layers separated. The water layer was extracted with 3, 50 ml portions of CHCl 3 and the combined CHCl 3 extract was dried over MgSO 4 and evaporated to give a residue. The residue was dissolved in 25 ml methanol, treated with charcoal, filtered and slowly diluted with 3 liters of anhydrous ether. Upon stirring for 72 hours there was obtained 2.21 g white solids, mp 164°-167° C. The combination of the filtrate and washings from the above solids was evaporated to dryness and the residue again heated under reflux in 70 ml EtOH containing 40 ml conc. HCl. Chloroform extraction followed by treatment of the extract evaporation residue with methanol/ether as before, yielded 3.7 g solids, mp 161°- 164° C., combined yield 21%.
Anal. Calc'd for C 16 H 21 NOS 2 .HCl: N, 4.07; Cl, 10.31; S, 18.7. Found: N, 3.79; Cl, 9.45; S, 18.2.
EXAMPLE 38
Benzylamine,α-t-butyl-p-methoxy-N-[4-(methyl-1,3-dithiol-2-ylidene]
A stirred slurry, containing 2 g of the compound of Example 34, in 50 ml distilled water, was slowly neutralized with 25% NaOH with cooling. The mixture was treated with 50 ml ethyl ether, the ether layer was separated and was washed with water until neutral, dried over MgSO 4 and evaporated in vacuo to give 1.6 g colorless, viscous oil, yield 80%, n D 25 1.5851.
Anal. Calc'd for C 16 H 21 NOS 2 : C, 62.5; H, 6.88; S, 20.9. Found: C, 62.8; H, 6.87; S, 20.5.
EXAMPLE 39
Benzeneethaneamine, N-(4-methyl-1,3-Dithiol-2-ylidene)
To a stirred slurry containing 12.12 g (0.1 mol) phenethylamine, 15.4 g (0.1 mol) 25% sodium hydroxide in 100 ml water was added 7.7 g (0.1 mol) carbon disulfide at 0°-10° C. over ˜5 minutes. To the resulting solution was added 12.2 g (0.11 mol) 2,3-dichloropropene at 20°-25° C. and the mixture allowed to stir overnight at 25°-30° C. The two-phase mixture was extracted with 50 ml of ether, the ether solution separated, dried over MgSO 4 and evaporated in vacuo to give 20.3 g amber oil. The oil was dissolved in 70 ml ethanol, 40 ml conc. HCl added and the mixture heated under reflux for six hours. After cooling and standing overnight the mixture was vacuum treated to remove the ethanol and excess HCl and the residue treated with benzene three times to azeotrope the water. The resulting residue was treated with ethyl ether, stirred two hours and filtered to yield 11.0 g light tan crystals, mp 80° -106° C. The crude salt, (10 g) was dissolved in 50 ml water, neutralized with 25% NaOH and the free base taken up in ether. The ether solution was washed until neutral, dried and evaporated to give 7.8 g amber oil which was purified by HPLC on silica gel using toluene as eluant. There was obtained 6.0 g, n D 25 1.5990, yield 40%.
Anal. Calc'd for C 12 H 13 NS 2 : C, 61.2; H, 5.57; N, 5.95; S, 27.3. Found: C, 61.4; H, 5.60; N, 5.90; S, 27.1.
Table III describes other compounds of the invention prepared in accordance with the procedure described in Examples 33-39.
TABLE III__________________________________________________________________________ ##STR34##Example AnalysisNo. Empirical R Calc'd Found Mp °C./n.sub.D.sup.25° % Yield__________________________________________________________________________40 C.sub.14 H.sub.17 NS.sub.2.HCl ##STR35## C, 56.1; H, 6.05; N, 4.67; S, 21.4 56.1 6.06 4.65 21.3 160-163 3341 C.sub.16 H.sub.21 NS.sub.2.HCl ##STR36## N, 4.27; Cl, 19.5; S, 10.8; 4.11 19.3 10.7 150-152 1642 C.sub.13 H.sub.15 NS.sub.2.HCl ##STR37## C, 54.6; H, 5.64; N, 4.90 S, 22.4; 54.7 5.67 4.96 22.3 161-164 543* C.sub.13 H.sub.15 NS.sub.2 ##STR38## C, 62.6; H, 6.06; N, 5.62; S, 25.7 62.5 6.07 5.64 25.7 1.5973 1444* C.sub.13 H.sub.15 NS.sub.2 ##STR39## C, 62.6; H, 6.06 N, 5.62; S, 25.7; 62.5 6.10 5.62 25.6 1.5892 8*45 C.sub.11 H.sub.10 ClNS.sub.2 ##STR40## C, 51.6; H, 3.94 N, 5.48; 51.8 3.95 5.51 1.6266 1346* C.sub.11 H.sub.10 ClNS.sub.2 ##STR41## C, 51.6; H, 3.94; N, 5.48; S, 51.8 4.00 5.51 25.0 55-60° 547 C.sub.14 H.sub.17 NS.sub.2 ##STR42## C, 63.8; H, 6.51; S, 24.3; 63.7 6.54 24.2 1.5828 848* C.sub.12 H.sub.12 ClNS.sub.2 ##STR43## N, 5.19; Cl, 13.1; S, 23.8; 5.19 13.3 23.7 1.6083 27__________________________________________________________________________ *Isolated by HPLC
EXAMPLE 49
Benzylamine-α-methyl-N-[5-(phenyl)-1,3-oxathiol-2-ylidene]
A stirred solution containing 10.0 g (0.048 mol) of 1-(α-methyl)benzyl-3,3-dimethylthiourea and 10.0 g (0.05 mol) of 97% α-bromoacetophenone in 100 ml dioxane was heated under reflux for 17 hours. The hot mixture was filtered, the filtrate was allowed to cool and then filtered again to remove a small amount of hygroscopic acids. Evaporation of the filtrate gave 15.2 g dark amber viscous oil which was taken up in ethyl ether and the solution washed with water until neutral, dried and evaporated to give 10.9 g dark brown oil which was purified by chromatography on silica gel using pet. ether/benzene yielding 3.5 g (12.5%) mp 67°-70° C. A sample was crystallized from pentane, mp 70°-72° C.
Anal. Calc'd for C 17 H 15 NOS: C, 72.6; H, 5.37; N, 4.98; S, 11.4. Found: C, 72.6; H, 5.37; N, 4.95; S, 11.4.
EXAMPLE 50
5-Benzeneamine, N-(5-phenyl-1,3-oxathiol-2-ylidene)
This compound was prepared according to the procedure described in Example 49 except that 1-phenyl-3,3-dimethylthiourea was used; the final product melted at 135°-136° C.
EXAMPLE 51
Benzylamine-N-(1,3-dithian-2-ylidene)
To a stirred solution of 10.7 g (0.1 mol) benzylamine in 100 ml DMF there was added 20 ml 10 N KOH at 25°-30° C. with ice bath cooling, followed by the addition of 7.6 g (0.1 mol) carbon disulfide. The resulting yellow solution was stirred at 25°-30° C. for one-half hour. 1,3-dibromopropane, 20.2 g (0.1 mol), was added dropwise to the above solution causing the temperature to rise slowly to 38° C. with precipitation of white solids. The mixture was stirred for 2.5 hours, chilled in an ice bath and filtered to give 19.7 g. The solid was treated with chloroform and water and the organic layer dried over MgSO 4 and solvent evaporated to yield 3.3 g, 10% yield, mp 125°-127.5° C.
Anal. Calc'd for C 11 H 13 NS 2 : C, 59.2; H, 5.87; S, 28.7. Found: C, 59.1; H, 5.88; S, 28.7.
EXAMPLE 52
o-Toluidine, 4-chloro-N-(1,3-dithietan-2-ylidene)Hydrochloride
o-Toluidine, 4-chloro-N-(1,3-dithietan-2-ylidene) was prepared according to the procedure described in U.S. Pat. No. 3,954,801, mp. 165.5°-169° C.
Anal. Calc'd for C 9 H 8 ClNS 2 .HCl: N, 5.27; Cl, 26.6; S, 24.1. Found: C, 5.37; Cl, 26.5; S, 23.8.
EXAMPLE 53
o-Toluidine, 4-chloro-, N-(1,3-dithietan-2-ylidene)
o-Toluidine, 4-chloro-, N-(1,3-dithietan-2-ylidene) was prepared by neutralizing an aqueous solution of the compound of Example 52 with 25% NaOH. An off-white solid was recovered which melted at 41°-44° C.
Anal. Calc'd for C 9 H 8 ClNS 2 : N, 6.10, Cl, 15.4; S, 27.9. Found: N, 6.19; Cl, 15.5; S, 27.4.
The following examples are presented to illustrate the safening effectiveness of the compounds of the present invention as well as the various embodiments of the invention. These examples are presented as being illustrative of the novel usages of the invention and are not intended to be a limitation as to the scope thereof.
EXAMPLE 54
Aluminum pans or plastic pots are filled with prepared Ray silt loam soil and compacted to a depth of 1/2 inch from the top of the container. The pans or pots are then planted with seeds or vegetative propagules of the desired plant species. Soil cover layers, of prepared Ray silt loam, are sequentially treated with antidote and herbicide. The antidote, dissolved in a suitable solvent, is applied to the soil cover layer followed by herbicide application. The desired concentration of herbicide is formulated as a solution, emulsifiable concentration or wettable powder in a suitable solvent. After antidote and herbicide are applied to the soil cover layer, the combination is thoroughly incorporated into the soil cover layer by stirring or shaking. The soil cover layers are then placed on the pre-seeded pans or pots and the pans or pots are transferred to a greenhouse bench where they are watered from below. Two to four weeks after application of the antidote and herbicide combination, the results are observed and recorded. Pans or pots treated only with antidote or herbicide are prepared and treated as described above. The results observed from the pans or pots provide the measure of plant inhibition due to antidote and herbicide alone. The "safening effect" of the antidote is calculated as follows: [% Plant Inhibition due to Herbicide+% Plant Inhibition due to Antidote--% Plant Inhibition due to Antidote/Herbicide Combination].
Table IV summarizes the results obtained when the compounds of the invention were tested in accordance with the procedure of Example 54 utilizing triallate as the herbicide.
TABLE IV______________________________________ Rate of Rate ofCompound of Triallate Antidote Safening EffectExample No. (lb/A) (lb/A) Rice Sorghum Wheat______________________________________3 0.25 8.0 70 85 8515 0.375 8.0 34 70 334 0.25 8.0 65 70 7514 0.25 4.0 * * *14 0.375 8.0 * * 3835 0.25 4.0 40 * 2535 0.375 8.0 * * *36 0.25 8.0 65 75 457 0.375 8.0 * * *2 0.375 8.0 * 55 2820 0.375 8.0 34 90 3321 0.375 8.0 20 70 436 0.375 8.0 * 83 3052 0.375 8.0 40 93 4053 0.375 8.0 * 93 258 0.5 8.0 * 48 2017 0.5 8.0 35 85 3050 0.5 8.0 * * *49 0.5 8.0 65 78 559 0.5 8.0 * * 2022 0.5 8.0 55 87 5010 0.5 8.0 * 22 7023 0.5 8.0 25 97 5024 0.5 8.0 25 90 2525 0.5 8.0 20 65 *11 0.5 8.0 * 63 *16 0.5 8.0 * 38 *12 0.5 8.0 20 30 8040 0.5 8.0 20 79 485 0.5 8.0 23 45 *13 0.5 8.0 * * *41 0.5 8.0 * 55 *26 0.5 8.0 30 * *37 0.5 8.0 * 30 *38 0.5 8.0 * * *42 0.5 8.0 20 * 4347 0.5 8.0 * * *27 0.5 8.0 90 85 6548 0.5 8.0 -- 82 8448 0.5 8.0 * 80 *28 0.5 8.0 * 58 *43 0.5 8.0 * 30 2829 0.5 8.0 40 * *30 0.5 8.0 * 20 6018 0.5 8.0 21 82 1631 0.5 8.0 * * *32 0.5 8.0 50 * *39 0.5 8.0 * * *19 0.5 8.0 * 48 *44 0.5 8.0 * 68 *33 0.5 8.0 * 67 3534 0.5 8.0 * * *45 0.5 8.0 * 40 *46 0.5 8.0 * * *51 0.5 8.0 50 90 *21 0.125 8.0 20 35 28 0.25 8.0 * 75 50 0.5 8.0 * 47 34 1.0 8.0 * * *52 0.125 8.0 * 88 20 0.25 8.0 30 77 * 0.5 8.0 33 22 * 1.0 8.0 * * *49 0.125 8.0 * * 20 0.25 8.0 45 40 60 0.5 8.0 53 60 58 1.0 8.0 24 68 2530 0.25 8.0 25 65 50 0.5 8.0 20 * * 1.0 8.0 * * * 2.0 8.0 * * *27 0.25 8.0 30 84 70 0.50 8.0 55 50 87 1.0 8.0 66 50 28 2.0 8.0 55 20 *______________________________________ *Safening effect was between 0 and 19
Following the procedure of Example 54, the compounds of the invention were tested on rice, sorghum and wheat utilizing the acetanilide herbicide alachlor. The results are summarized in Table V.
TABLE V______________________________________ Rate of Rate ofCompound of Alachlor Antidote Safening EffectExample No. (lb/A) (lb/A) Rice Sorghum Wheat______________________________________3 1.0 8.0 35 20 *15 2.0 8.0 * 42 404 1.0 8.0 25 * *14 2.0 8.0 93 * *14 2.0 4.0 * * *35 2.0 8.0 43 * *35 2.0 4.0 28 * *36 2.0 8.0 78 45 437 2.0 8.0 * * *2 2.0 8.0 * * *20 2.0 8.0 * 70 4021 2.0 8.0 * * *6 2.0 8.0 33 * *52 2.0 8.0 * * *53 2.0 8.0 48 20 *8 2.0 8.0 28 * 2317 2.0 8.0 * 35 2550 2.0 8.0 * * *49 4.0 8.0 * * 209 4.0 8.0 * * *22 4.0 8.0 * 25 *10 4.0 8.0 * * *23 4.0 8.0 * 25 2024 4.0 8.0 * * *25 4.0 8.0 * * *11 4.0 8.0 * * *16 4.0 8.0 * * *12 4.0 8.0 * * *40 4.0 8.0 * * *5 4.0 8.0 35 * *13 4.0 8.0 * * *41 4.0 8.0 * * *26 4.0 8.0 * * *37 4.0 8.0 * * *38 4.0 8.0 * * 2042 4.0 8.0 * * *47 4.0 8.0 * * *27 4.0 8.0 * * *48 2.0 8.0 * * *48 4.0 8.0 -- * *28 2.0 8.0 * 43 *29 2.0 8.0 * * *43 2.0 8.0 * 20 *30 2.0 8.0 31 * *18 2.0 8.0 * * *31 2.0 8.0 * * *32 2.0 8.0 * * *39 2.0 8.0 * * 2519 2.0 8.0 40 * *44 2.0 8.0 * * *33 2.0 8.0 20 * *34 2.0 8.0 * * *45 4.0 8.0 * 20 *46 4.0 8.0 * * *51 4.0 8.0 * * *3 0.5 8.0 55 1.0 8.0 50 2.0 8.0 20 4.0 8.0 4036 0.5 8.0 35 1.0 8.0 50 2.0 8.0 63 4.0 8.0 6420 0.5 8.0 78 1.0 8.0 64 2.0 8.0 34 4.0 8.0 2017 0.0625 8.0 * 0.25 8.0 43 1.0 8.0 54 4.0 8.0 *22 0.5 8.0 65 1.0 8.0 63 2.0 8.0 77 4.0 8.0 *23 0.5 8.0 70 1.0 8.0 48 2.0 8.0 22 4.0 8.0 *28 0.5 8.0 40 1.0 8.0 26 2.0 8.0 * 4.0 8.0 *43 0.5 8.0 * 1.0 8.0 40 2.0 8.0 20 4.0 8.0 40______________________________________ *Safening effect was between 0 and 19
Utilizing the procedure of Example 54, the compounds of the invention were tested on rice, sorghum and wheat against the acetanilide herbicide butachlor. The results are summarized in Table VI.
TABLE VI______________________________________ Rate of Rate ofCompound of Butachlor Antidote Safening EffectExample No. (lb/A) (lb/A) Rice Sorghum Wheat______________________________________3 4.0 8.0 30 35 2015 4.0 8.0 20 58 384 4.0 8.0 35 35 *14 4.0 8.0 * * *14 4.0 8.0 * * *35 4.0 8.0 23 * 2335 4.0 8.0 25 * *36 4.0 8.0 68 28 407 4.0 8.0 * 25 *2 4.0 8.0 35 * 2320 4.0 8.0 55 40 5321 4.0 8.0 20 25 *6 4.0 8.0 * 53 *52 4.0 8.0 * * *53 4.0 8.0 20 * 388 4.0 8.0 * * 3017 4.0 8.0 73 50 2550 4.0 8.0 * 30 *49 4.0 8.0 * 38 *9 4.0 8.0 * 30 2022 4.0 8.0 * 55 3810 4.0 8.0 * * *23 4.0 8.0 * 60 *24 4.0 8.0 20 60 4525 4.0 8.0 * * *11 4.0 8.0 * 58 *16 4.0 8.0 * * 6012 4.0 8.0 * 35 *40 4.0 8.0 * 30 *5 4.0 8.0 55 * 2813 4.0 8.0 20 * *41 4.0 8.0 * * *26 4.0 8.0 * 23 *37 4.0 8.0 20 * *38 4.0 8.0 * * *42 4.0 8.0 25 * 4847 4.0 8.0 * * 3327 4.0 8.0 33 * *48 4.0 8.0 * 25 2048 4.0 8.0 -- * 3528 4.0 8.0 * * 3529 4.0 8.0 * * *43 4.0 8.0 38 32 2530 4.0 8.0 25 * 3318 4.0 8.0 34 * 3531 4.0 8.0 39 * *32 4.0 8.0 20 30 2039 4.0 8.0 * * *19 4.0 8.0 * * *44 4.0 8.0 25 * *33 4.0 8.0 55 * 2034 6.0 8.0 * * 2545 6.0 8.0 25 * *46 6.0 8.0 68 23 *51 6.0 8.0 35 * 40______________________________________ *Safening effect was between 0 and 19
The antidotes of the present invention may also be applied to the crop seed prior to planting. This is often a desirable mode of application as relatively small amounts of antidote are used compared to preemergence soil incorporation of antidote. The following examples describe the use of the antidote compounds of the present invention as seed treatments in greater detail.
EXAMPLE 55
Toluene solutions or suspensions of antidote are applied to the crop seed at the desired seed treatment concentration. Untreated (control) and treated seeds were planted in 91/2×51/4×23/4 inch deep pans containing Ray silt loam soil. Soil cover layers (450 gm) were sprayed with the desired concentration of herbicide using a belt sprayer (20 gpa), incorporated and placed on pre-seeded pans. The pans were given 1/4 inch of overhead water and transferred to greenhouse benches. The pans were sub-irrigated as required during the remainder of the test. Observations were made 21/2 to 3 weeks after treatment and the results recorded. The amount of antidote applied to the crop seed is calculated on % w/w basis defined as 1 part of antidote per 1000 parts of crop seed. The observations made and recorded in accordance with the above procedure utilizing triallate as the herbicide are shown in Table VII.
The results summarized in Table VII are shown as % Inhibition for untreated and teated seeds at varying rates of triallate herbicide and antidote. A--indicates that a reduction in expected inhibition occurred. That is, if "safening effect" were calculated, 20 units or greater "safening" occurred. The protection or "safening" afforded the crop plant by treatment of the crop seed with the "antidotal" compounds of the invention may be calculated as follows:
% Inhibition of Crop Plant (No Seed Treatment)-% Inhibition of Crop Plant (Seed Treatment).
TABLE VII______________________________________ Seed Treat- ment Com-Trial- poundlate ofRate Example % Crop Inhibition*Lb/A No. Crop Seed Treatment Conc., % W/W______________________________________ 0 1/6 1/8 1/4 1/2 1______________________________________0 1/16 1/8 1/4 1/2 1 2 ##STR44## ##STR45## 0 10 53 88 99 100 100 0 5 0- 0- 5- 10- 48- 0 0 0- 0- 10- 0- 35- 10 5 0- 0- 10- 0- 20- 0 0 0- 0- 0- 5- 25- 3 0 0- 5- 13- 8- 15-______________________________________ 0 1/2 1 2 4______________________________________0 1/16 1/8 1/4 1/2 1 2 4 ##STR46## ##STR47## 0 0 23 70 99 99 100 100 0 0 0- 0- 0- 0- 0- 30- 0 0 0- 0- 0- 0- 10- 58- 10 23 8- 5- 8- 20- 13- 20- 18 13 23 20- 18- 8- 15- 30-0 1/16 1/8 1/4 1/2 1 2 4 ##STR48## ##STR49## 0 5 28 65 93 95 98 100 0 0 10 0- 0- 0- 0- 23- 5 10 0- 3- 0- 5- 10- 20- 25 23 23- 20- 30- 28- 38- 40- 28 23 25- 40- 15- 30- 35-______________________________________ 48- 0 1/32 1/8 1/2______________________________________0 1/16 1/8 1/4 1/2 1 2 ##STR50## ##STR51## 0 5 28 60 88 99 100 0 5 0- 0- 8- 20- 78- 0 0 0- 0- 0- 8- 55- 0 5 0- 0- 0- 10- 63-0 1/16 1/8 1/4 1/2 1 2 ##STR52## ##STR53## 0 10 40 65 95 98 99 0 0 10 40 60 80 95 0 0 5- 10- 20- 55- 65- 10 15 20- 40- 40- 45- 55-0 1/16 1/8 1/4 1/2 1 2 ##STR54## ##STR55## 0 5 18 70 98 99 99 0 0 5 0- 5- 35- 80 0 0 0 0- 0- 13- 40- 0 5 0 0- 0- 20- 25-______________________________________ 0 1/16 1/4 1______________________________________0 1/128 1/64 1/32 1/16 1/8 1/4 ##STR56## ##STR57## 0 0 40 65 93 95 100 0 0 8- 5- 60- 88 99 0 0 3- 8- 60- 75- 86- 0 0 3- 23- 53- 80 980 1/128 1/64 1/32 1/16 1/8 1/4 ##STR58## ##STR59## 0 0 28 88 98 100 100 0 0 5- 5- 25- 99 100 5 0 10- 0- 18- 80- 92 3 0 5- 3- 40- 73- 900 1/8 1/4 1/2 1 2 4 ##STR60## ##STR61## 0 0 15 78 95 100 100 0 0 0 28- 83 95 99 0 0 0 3- 25- 70- 93 0 0 0 8- 35- 35 68-0 1/8 1/4 1/2 1 2 4 ##STR62## ##STR63## 0 0 15 75 90 99 100 0 0 0 18- 30- 83 100 0 0 0 3- 5- 53- 90 0 0 0 3- 10- 68- 78______________________________________ 0 1/8 1/4______________________________________0 1/16 1/8 1/4 1/2 1 2 4 ##STR64## ##STR65## 0 0 28 53 92 100 100 100 0 0 0- 0- 0- 0- 53- 68- 0 0 10- 0- 8- 8- 15- 78-0 1/16 1/8 1/4 1/2 1 2 4 ##STR66## ##STR67## 0 0 0 20 40 97 99 100 0 0 0 0- 0- 18- 68- 88- 0 0 0 0- 5- 13- 80- 85______________________________________ *Data reported is average of two replicates -Denotes less than expected inhibition, i.e., "safening" occurred.
The compound of Example 3, Benzylamine-(α-methyl)-N-[4-(dichloromethylene)-1,3-dithiolan-2-ylidene]Hydrochloride was further tested as a seed treatment on several wheat varieties utilizing triallate as the herbicide according to the procedure of Example 56.
EXAMPLE 56
A toluene solution or suspension of the compound of Example 3 was applied to selected wheat varieties to obtain desired seed treatment concentrations. Untreated wheat seed and wheat seed treated with three concentrations of the compound of Example 3 were planted in 91/2×51/4×23/4 inch deep pans containing Ray silt loam soil. Cover layers of soil (450 gm) were sprayed with triallate, incorporated and placed on pre-seeded pans. The pans were given 1/2 inch of overhead water and transferred to greenhouse benches where they were subirrigated as required during the remainder of the test. The results are summarized in Table VIII.
TABLE VIII______________________________________Triallate % Wheat Inhibition*Rate, Wheat Seed Treatment Conc. (% W/W)Lb/A Variety 0 1/16 1/4 1______________________________________0 Olaf semidwarf hard 0 0 0 0 red spring1/16 Olaf semidwarf hard 0 0 0 0 red spring1/8 Olaf semidwarf hard 3 0 0 0 red spring1/4 Olaf semidwarf hard 18 0 0 0 red spring1/2 Olaf semidwarf hard 78 0- 0- 0- red spring1 Olaf semidwarf hard 90 25- 23- 10- red spring2 Olaf semidwarf hard 100 60- 53- 40- red spring0 Nugaines white 0 15 40 60 winter1/16 Nugaines white 0 0 35 63 winter1/8 Nugaines white 10 10 43 60 winter1/4 Nugaines white 53 10- 25- 45- winter1/2 Nugaines white 85 10- 45- 35- winter1 Nugaines white 93 23- 50- 55- winter2 Nugaines white 100 58- 58- 58- winter0 Arthur 71 Soft red 0 0 0 0 Winter1/16 Arthur 71 Soft red 8 0 0 0 Winter1/8 Arthur 71 Soft red 33 0- 0- 0- Winter1/4 Arthur 71 Soft red 58 0- 0- 0- Winter1/2 Arthur 71 Soft red 98 0- 0- 15- Winter1 Arthur 71 Soft red 100 30- 0- 0- Winter2 Arthur 71 Soft red 100 93 18- 5- Winter0 Eagle hard red 0 0 0 5 winter1/16 Eagle hard red 0 0 0 0 winter1/8 Eagle hard red 3 0 0 0 winter1/4 Eagle hard red 53 0- 0- 0- winter1/2 Eagle hard red 99 0- 0- 0- winter1 Eagle hard red 100 5- 0- 5- winter2 Eagle hard red 100 53- 23- 25- winter0 Rolette durum 0 0 0 81/16 Rolette durum 0 0 0 81/8 Rolette durum 0 0 0 101/4 Rolette durum 5 0 0 01/2 Rolette durum 68 0- 0- 0-1 Rolette durum 73 10- 5- 0-2 Rolette durum 93 43- 43- 43-0 Waldron hard red 0 0 0 15 spring1/16 Waldron hard red 13 0 0 0- spring1/8 Waldron hard red 43 0- 0- 0- spring1/4 Waldron hard red 73 0- 0- 0- spring1/2 Waldron hard red 94 0- 0- 0- spring1 Waldron hard red 100 20- 13- 13- spring2 Waldron hard red 100 68- 53- 25- spring______________________________________ -Denotes less than expected inhibition, i.e., "safening" occurred. *Average of 2 replicates
EXAMPLE 57
A toluene solution or suspension of the compound of Example 3, Benzylamine-α-methyl-N-[4-(dichloromethylene)-1,3-dithiolan-2-ylidene]hydrochloride was applied to wheat to obtain the desired seed treatment concentration. Untreated downy brome, green foxtail, wild oats and wheat seed along with wheat seed treated with three concentrations of the compound of Example 3 were planted in 91/2×51/4×23/4 inch deep pans containing Ray silt loam soil. Triallate was applied to soil cover layers (450 gm) with the belt sprayer (20 gpa) and incorporated. The treated cover layers were placed on pre-seeded pans, the pans transferred to greenhouse benches and subirrigated.
TABLE IX______________________________________ % Wheat Inhibition % InhibitionTriallate Seed Treat. Conc. (% w/w) Grass WeedsRate, Lb/A 0 1/32 1/8 1/2 FT DB WO______________________________________-- 0 0 0 0 0 0 01/32 0 0 0 0 0 20 801/16 0 0 0 0 10 60 851/8 15 0 0 0 25 95 951/4 45 0- 0- 0- 55 95 991/2 90 0- 0- 0- 65 100 991 98 30- 0- 10- 70 100 1002 99 90 45- 35- 75 100 100______________________________________ FT = Green foxtail DB = Downy brome WO = Wild oats - Denotes less than expected inhibition, i.e., "safening" occurred.
EXAMPLE 58
Dichloromethane solutions or suspensions of test chemicals were applied to sorghum to obtain desired seed treatment concentrations. Untreated crabgrass, foxtail, barnyardgrass and sorghum along with sorghum treated with three concentrations of a chemical were planted in 91/2×51/4×23/4 inch deep pans containing Ray slit loam soil. Soil cover layers (450 gm) were placed on pre-seeded pans. Alachlor was applied to the soil surface with the belt sprayer (20 gpa). The pans were given 1/4 inch of overhead water, transferred to greenhouse benches and sub-irrigated as required for the duration of the test. The results are summarized in Table X.
TABLE X______________________________________Ala- Seed % Sorghumchlor Treatment Inhibition Seed % InhibitionRate, Compound Treat. Conc. % w/w Grass Weeds.sup.1Lb/A of Ex. No. 0 1/16 1/4 1 CG FT BYG______________________________________0 1/32 1/16 1/8 1/4 1/2 1 2 ##STR68## 0 85 90 95 100 98 98 99 0 0- 35- 80 85 85 95 95 0 0- 0- 0- 5- 50- 60- 70- 5 10- 10- 0- 10- 20- 35- 30- 0 60 90 95 99 99 100 100 0 98 98 99 99 100 100 0 98 100 100 100 100 100 1000 1/32 1/16 1/8 1/4 1/2 1 2 ##STR69## 0 15 30 80 95 98 99 100 5 35 0- 0- 75- 90 95 98 10 60 25 30- 50- 15- 45- 65- 95 95 100 95 90 90 100 95 0 80 85 99 99 100 100 100 0 98 99 99 100 100 100 0 99 99 100 100 100 100 1000 1/32 1/16 1/8 1/4 1/2 1 2 ##STR70## 0 5 20 40 90 100 100 100 0 0 10 0- 35- 45- 90 98 0 0 0 0- 5- 15- 25- 60- 55 50 70 50- 75- 75- 70- 80- 0 40 90 90 100 100 100 100 0 98 98 98 100 100 100 0 98 100 100 100 100 100 1000 1/32 1/16 1/8 1/4 1/2 1 2 ##STR71## 0 5 65 80 90 90 95 99 0 0 55 35- 80 95 90 98 0 0 20- 65 75 75 95 90 0 0 0- 10- 15- 30- 35- 70- 0 30 45 70 95 95 98 99 0 95 100 99 100 100 100 0 95 98 99 100 100 99______________________________________ 100 .sup.1 CG = Crabgrass FT = Green Foxtail BYG = Barnyardgrass -Denotes less than expected inhibition, i.e., "safening" occurred.
EXAMPLE 59
Dichloromethane solutions or suspensions of the compound of Example 36 were applied to rice to obtain desired seed treatment concentrations. Untreated and treated rice were pregerminated for 2 days on moist towels. Plastic pots (4×4×3 inches deep) were filled with 2 inches of Ray slit loam soil. Barnyard grass was seeded into a shallow trench and covered with soil. Butachlor was applied to the soil surface with the belt sprayer (20 gpa). Rice was seeded into flooded pots. The water level was lowered to the soil surface after 24 hours and maintained at this level for 5 days after which the pots were reflooded for the duration of the test. The results are summarized in Table XI.
TABLE XI______________________________________ % Inhibition, Avg 2 RepsButachlor Seed Treatment Water Seeded Barnyard-Rate, lb/A Concentration % w/w Rice grass______________________________________1/64 -- 38 671/16 -- 91 991/4 - 100 100-- 1/32 0 01/64 1/32 43 731/16 1/32 68- 1001/4 1/32 63- 100-- 1/8 10 01/64 1/8 23- 601/16 1/8 55- 1001/4 1/8 58- 100-- 1/2 65 01/64 1/2 60- 481/16 1/2 70- 921/4 1/2 68- 100______________________________________ -Denotes less than expected inhibition, i.e., "safening"occurred.
The antidotes of the present invention may be combined with thiocarbamate or acetanilide herbicides as a tank mix and applied to soil planted with crop seed. Examples 57 and 58 and Tables XII and XIII describe this aspect of the invention in greater detail. The data shown in Tables XII and XIII is reported as % Inhibition; the % "safening effect" may be readily calculated by the use of the following formula: [% Inhibition of Crop Plant Due to Herbicide+% Inhibition of Crop Plant Due to Antidote]--% Inhibition of Crop Plant Due to Antidote/Herbicide Combination.
EXAMPLE 60
Wheat and several weed species were planted in 4×4×3 inch deep plastic pots containing Ray slit loam soil. The chemical combinations were applied as tank mixtures to soil cover layers with the belt sprayer (20 gpa). The treated cover layers were shaken in plastic bags to incorporate the chemicals. The cover layers were placed on preseeded pots, the pots transferred to a greenhouse bench and sub-irrigated. The results are summarized in Table XII.
TABLE XII__________________________________________________________________________Trial- % Inhibition, Avg 2 Repslate Compound Antidote Ann. Barn-Rate of Example Rate Wild Downy Green Rye- Black yardlb/A No. Lb/A Wheat oats brome foxtail grass grass grass__________________________________________________________________________1/64 -- -- 0 50 58 01/16 -- -- 5 98 99 01/4 -- -- 68 100 100 201 -- -- 100 100 100 680 1/64 1/16 1/4 1 0 1/64 1/16 1/4 1 0 1/64 1/16 1/4 1##STR72## 1/4 1/4 1/4 1/4 1/4 1 1 1 1 1 4 4 4 4 4 0 0 8 43- 100 0 0 0 15- 98 0 0 0 0- 85 0 73 98 100 100 0 88 99 100 100 0 55 100 100 100 0 60 100 100 100 0 60 100 100 100 0 10- 68- 100 0 0 0 18 60 0 0 0 5 82 0 0 0 10 18-0 1/64 1/16 1/4 1 0 1/64 1/16 1/4 1 0 1/64 1/16 1/4 1##STR73## 1/4 1/4 1/4 1/4 1/4 1 1 1 1 1 4 4 4 4 4 0 0 0 25- 98 0 0 0 18- 90 0 0 0 5- 68- 10 88 100 100 100 30 95 100 100 100 0 75 100 100 10 53 100 100 100 0 53 100 100 100 0 45 70- 100 0 0 5 20 48- 0 0 0 13 25- 0 0 0 0- 5-0 -- -- 0 0 0 0 0 0 01/32 -- -- 0 85 65 0 65 33 01/16 -- -- 0 97 98 0 93 85 01/8 -- -- 38 99 99 8 98 94 01/4 -- -- 63 100 100 28 99 100 01/2 -- -- 95 100 100 50 100 100 00 1/32 1/16 1/8 1/4 1/2##STR74## 1/8 1/8 1/8 1/8 1/8 1/8 0 0 0 8- 63 83 0 85 98 100 100 100 0 68 93 100 100 100 0 0 0 3 30 45 0 53 89 93 99 100 0 43 83 99 99 100 0 0 0 0 0 00 1/32 1/16 1/8 1/4 1/2##STR75## 1/4 1/4 1/4 1/4 1/4 1/4 0 0 0 10- 50 83 0 75 97 99 100 100 0 63 90 100 100 100 0 0 0 0 18 35 0 50 73- 90 99 100 0 20 75 99 100 100 0 0 0 0 0 00 1/32 1/16 1/8 1/4 1/2##STR76## 1/2 1/2 1/2 1/2 1/2 1/2 0 0 0 0- 20- 60- 0 90 97 98 99 100 0 53 85 95 100 100 0 0 0 0 8- 20- 0 45- 35- 70- 94 99 0 28 53- 70- 99 100 0 0 0 0 0 0__________________________________________________________________________ - Denotes less than expected inhibition, i.e., "safening" occurred.
EXAMPLE 61
Sorghum, crabgrass, green foxtail and barnyardgrass were planted in 4×4×3 inch deep plastic pots containing Ray slit loam soil. Soil cover layers were placed on the preseeded pots. A combination of alachlor and the compound of Example 17 was applied as a tank mixture to the soil surface with the belt sprayer (20 gpa). The pots were given 1/4 inch of overhead water and transferred to greenhouse benches. The pots were subirrigated as required during the remainder of the test. The results are summarized in Table XIII.
TABLE XIII______________________________________Antidote % Inhibition, Avg. 2 repsAlachlor Rate Green BarnyardRate, Lb/A Lb/A Sorghum Crabgrass Foxtail Grass______________________________________1/32 - 0 18 88 601/8 - 10 63 93 971/2 - 68 94 99 1002 - 85 98 99 1000 1/8 0 0 0 01/32 1/8 0 18 75 431/8 1/8 8 55 98 971/2 1/8 50 83 99 1002 1/8 96 98 100 1000 1/2 0 0 0 151/32 1/2 0 13 73 15-1/8 1/2 5 65 95 981/2 1/2 45- 88 99 1002 1/2 94 98 100 1000 2 0 0 0 01/32 2 0 13 82 451/8 2 0 50 97 991/2 2 58 85 99 1002 2 75 97 99 100______________________________________ - Denotes less than expected inhibition, i.e., "safening" occurred. on water-seeded rice plants utilizing butachlor herbicide following the procedure of Example 62.
EXAMPLE 62
Plastic pots (4×4×3 inches deep) were filled with 2 inches of Ray slit loam soil. The combination treatments were applied sequentially to the soil surface with the belt sprayer (20 gpa). Pre-soaked rice (2 day duration) was seeded into flooded pots. The water level was lowered to the soil surface after 24 hours and maintained at this level for 5 days after which the pots were reflooded for the duration of the test. The results obtained when water-seeded rice was treated in the manner described above are summarized in Table XIV.
TABLE XIV______________________________________ Rate of Rate ofCompound of Herbicide AntidoteExample No. (lb/A) (lb/A) Safening Effect______________________________________ ##STR77## 1/64 1/16 1/4 ##STR78## * 35 * ##STR79## 1/64 1/16 1/4 ##STR80## 26 23 * ##STR81## 1/64 1/16 1/2 ##STR82## 26 60 * ##STR83## 1/32 1/8 1/2 ##STR84## * 44 37 ##STR85## 1/16 1/4 1 ##STR86## 32 * *______________________________________ *Safening effect was between 0 and 19.
Compounds of Examples 17, 20, 31, 34, 43 and 51 exhibited less than 20 units of safening when tested at 1/64, 1/16 and 1/4 pounds per acre.
The above examples illustrate that the 2-imino-1,3-dithio and 1,3-oxathio derivatives of the present invention are useful in reducing herbicidal injury to crop plants, for example, sorghum, rice and wheat. The safening agents may be applied to the plant locus as a mixture, i.e., a mixture of a herbicidally effective amount of thiocarbamate or acetanilide herbicide and a safening effective amount of safening agent, or sequentially, i.e., the plant locus may be treated with an effective amount of the herbicide followed by a treatment with the safening agent or vice versa. The ratio of herbicide to safening agent may vary depending upon the crop to be protected, weeds to be inhibited, herbicide used, etc., but normally a herbicide to safening agent ratio ranging from 1:25 to 25:1 (preferably 1:5 to 5:1) parts by weight may be employed.
The herbicide, safening agent or mixture thereof may be applied to the plant locus alone or the herbicide, safening agent or mixture thereof may be applied in conjunction with a material referred to in the art as an adjuvant in liquid or solid form. Mixtures containing the appropriate herbicide and safening agent usually are prepared by admixing said herbicide and safening agent with an adjuvant including diluents, extenders, carriers and conditioning agents to provide compositions in the form of finely-divided particulate solids, granules, pellets, wettable powders, dusts, solutions and aqueous dispersions or emulsions. Thus, the mixture may include an adjuvant such as a finely-divided particulate solid, a solvent liquid of organic origin, water, a wetting agent, dispersing agent, or emulsifying agent or any suitable combination of these.
When applying the herbicide, safening agent or mixture thereof to the plant locus, useful finely-divided solid carriers and extenders include, for example, the talcs, clays, pumice, silica, diatomaceous earth, quartz, Fullers earth, sulfur, powdered cork, powdered wood, walnut flour, chalk, tobacco dust, charcoal and the like. Typical liquid diluents useful include for example, Stoddard solvent, acetone, alcohols, glycols, ethyl acetate, benzene and the like. Such compositions, particularly liquids and wettable powders, usually contain as a conditioning agent one or more surface-active agents in amounts sufficient to render a given composition readily dispersible in water or in oil. By the term "surface-active agent", it is understood that wetting agents, dispersing agents, suspending agents and emulsifying agents are included therein. Such surface-active agents are well known and reference is made to U.S. Pat. No. 2,547,724, Columns 3 and 4, for detailed examples of the same.
Compositions of this invention generally contain from about 5 to 95 parts herbicide and safening agent, about 1 to 50 parts surface-active agent and about 4 to 94 parts solvent, all parts being by weight based on the total weight of the composition.
The application of the herbicide, safening agent or mixture thereof in a liquid or particulate solid form can be carried out by conventional techniques utilizing, for example, spreaders, power dusters, boom and hand sprayers, spray dusters and granular applications. The compositions can also be applied from airplanes as a dust or spray. If desired, application of the compositions of the invention to plants can be accomplished by incorporating the compositions in the soil or other media.
The above examples also illustrate that the crop may be protected by treating the crop seed with an effective amount of safening agent prior to planting. Generally, small amounts of safening agent are required to treat such seeds. A weight ratio of as little as 0.031 parts of safener per 1000 parts of seed may be effective. The amount of safener utilized in treating the seed may be increased if desired. Generally, however, a weight ratio of safening agent to seed weight may range from 0.1 to 10.0 parts of safening agent per 1000 parts of seed. The determination of the effective amount of safening agent required is well within the skill of the art.
Since only a very small amount of active safening agent is usually required for the seed treatment, the compound preferably is formulated as a powder or an emulsifiable concentrate which can be diluted with water by the seed treater for use in the seed treating apparatus. Of course, under certain conditions, it may be desirable to dissolve the safening agent in an organic solvent for use as a seed treatment or the pure compound alone may be used under properly controlled conditions.
There are thus also provided by this invention novel seed treating compositions containing one or more of the described active safening agents intimately dispersed in an inert carrier or diluent for the intended use. Such carriers may be either solids, such as talc, clay, diatomaceous earth, sawdust, calcium carbonate, and the like or liquids such as water, kerosene, acetone, benzene, toluene, xylene, and the like in which the active agent may be either dissolved or dispersed. Emulsifying agents are advisably used to achieve a suitable emulsion if two immiscible liquids are used as a carrier. Wetting agents may also be used to aid in dispersing the active safening agent in liquids used as a carrier in which the agent is not completely soluble. Emulsifying agents and wetting agents are sold under numerous tradenames and may be either pure compounds, mixtures of compounds of the same general groups, or they may be mixtures of compounds of different classes. Typical satisfactory surface-active agents which may be used are alkali metal higher alkylarylsulfonates such as sodium dodecylbenzenesulfonate and the sodium salts of alkylnaphthalenesulfonic acids, fatty alcohol sulfates such as the sodium salts of monoesters of sulfuric acid with n-aliphatic alcohols containing 8-18 carbon atoms, long chain quaternary ammonium compounds, sodium salts of petroleum-derived alkylsulfonic acids, polyethylene sorbitan monooleate, alkylaryl polyether alcohols, water-soluble lignin sulfonate salts, alkali-casein compositions, long chain alcohols usually containing 10-18 carbon atoms, and condensation products of ethylene oxide with fatty acids, alkylphenols and mercaptans.
While the compounds of the present invention, which are described hereinabove, generally safen crop plants, especially cereal crop plants, against the herbicidal effect of thiocarbamate and acetanilide herbicides, those skilled in the art will appreciate, from the biological data reported above, that various of the compounds of the present invention are most advantageously employed in a method of safening specific crop plants against either thiocarbamate or acetanilide herbicides. The following specific embodiments of the present invention are expressly contemplated herein (the limitations previously noted in the description of the invention likewise apply to the specific embodiments):
A. A method of reducing injury to rice, sorghum and wheat injured by thiocarbamate herbicides, especially triallate, using a safening effective amount of the compounds of the formula:
R--N=A
or an agriculturally acceptable acid addition salt thereof, wherein R is lower alkyl, ##STR87## R 1 is hydrogen, methyl, ethyl or isopropyl; X and Y are independently equal to lower alkyl, lower alkoxy or halogen; ##STR88## R 2 is hydrogen or methyl; R 3 is hydrogen or chloro;
R 4 is hydrogen, methyl or phenyl.
B. A method or reducing injury to sorghum plants injured by acetanilide herbicides, especially alachlor, using a safening effective amount of compounds of the formula ##STR89## or an agriculturally acceptable acid addition salt thereof, wherein R 1 is hydrogen or methyl; X is hydrogen, lower alkyl or lower alkoxy; ##STR90## R 2 is hydrogen or methyl; provided that when A is ##STR91## X must equal hydrogen.
C. A method of reducing injury to rice plants injured by acetanilide herbicides, especially butachlor, using a safening effective amount of compounds of the formula: ##STR92## or an agriculturally acceptable acid addition salt thereof, wherein R 1 is hydrogen, methyl, ethyl, isopropyl, butyl or isobutyl; X and Y are independently equal to lower alkyl, lower alkoxy or halogen; ##STR93## R 2 is hydrogen or methyl; R 3 is hydrogen or chloro; provided that when A is ##STR94## R 1 cannot equal isopropyl.
Although this invention has been described with respect to specific modifications, the details thereof are not to be construed as limitations, for it will be apparent that various equivalents, changes and modifications may be resorted to without departing from the spirit and scope thereof and it is understood that such equivalent embodiments are intended to be included herein.
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Derivatives of 2-imino-1,3-dithiolane, 1,3-dithiole, 1,3-dithiane, 1,3-dithietane and 1,3-oxathiole have been found to reduce herbicidal injury to crop plants due to thiocarbamate and acetanilide herbicides.
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Applicant inventor is the inventor of Transcutaneous Energy Transfer Device, disclosed in related U.S. patent application Ser. No. 08/685,813 filed on Jul. 24 th , 1996, now U.S. Pat. No. 5,755,748.
FIELD OF THE INVENTION
This invention relates to the field of medical devices. In particular, the present invention relates to transcutaneous energy transfer (TET) devices.
BACKGROUND OF THE INVENTION
A TET device is a device for providing electrical power to an implanted mechanical or electrical medical device, such as a bone growth stimulator, muscle stimulator, prosthetic heart or a ventricular assist device, without having to breach the skin to lead conducting wires therethrough.
In U.S. Pat. No. 5,350,413 John Miller discloses a TET device with a high-energy transfer efficiency. Such a device allows for efficient transfer of energy between two coils having fixed spacing. Unfortunately, as one coil is located within a body and another coil is located outside the body, maintaining coil separation at a constant distance is difficult. Changes in coil spacing result in variation of the induced voltage and, as the distance increases, the power transfer efficiency drops off rapidly.
In an article entitled "Development of an Autotuned Transcutaneous Energy Transfer System," John Miller, G. Belanger, and T. Mussivand suggest an autotuning circuit to overcome this problem. The autotuning circuit compares various voltages and currents present within a driving circuit external to the body to determine a tuning requirement. Such tuning enables the tuning of energy transfer where the coil spacing varies.
It has been found that the autotuning function disclosed addresses the problem of power coupling efficiency, but fails to address a further problem of internal voltage control. In driving implanted medical devices, energy coupling efficiency and voltage control are separate but related issues to address. Better coupling efficiency results in lower operating cost and improved battery life. Voltage control results in improved device operation and increased safety. In fact, some devices will fail from excessive applied voltage.
Further, it has been found that efficiency is affected by several factors some of which include power coupling related factors such as spacing and load related factors such as medical device load requirements or faults. Unfortunately, autotuning does not address the issue of providing additional energy when required by a medical device.
It has also been found, that prolonged exposure to electromagnetic fields results in damage to human skin. Resulting damage is not believed to be linearly related to the electromagnetic field strength and exposure time. It is believed that high-energy electromagnetic fields above a certain threshold damage human skin and adjacent tissue significantly more rapidly than low energy electromagnetic fields. Since a TET device provides energy to an implanted system and some of these implanted systems require significant power, the damage to tissue such as human skin is a significant drawback to extended use of TET devices. Reducing the electromagnetic field strength and/or reducing exposure time increases tissue longevity.
Two common approaches are known for addressing the problem of tissue damage. The first, skin grafting, is a surgical technique wherein dead tissue is replaced with healthy tissue from another area of a patient's body. Surgical techniques of this type are generally, not desirable. The second technique involves the design and implantation of lower power devices. Unfortunately, a device such as a heart pump requires significant power even when efficiently implemented.
It would be advantageous to provide a TET system that was less prone that the prior art to the problems of tissue damage.
In U.S. Pat. No. 5,350,413, John Miller further discloses an IR telemetry module for providing bidirectional communications. It is known that infra red telemetry is affected by skin pigmentation. As a transceiver disclosed by John Miller is implanted beneath a layer of skin, such considerations are important. It has been found that highly pigmented skin attenuates IR signals and renders a system as disclosed by John Miller substantially unworkable. Further, dirt and other obstructions like clothing or casings affect IR telemetry and can render it inoperable. For a television remote control, this is an acceptable limitation; for medical devices required by an individual, an inoperable TET is unacceptable.
Limitations are inherent in an IR telemetry link. IR is an optical communications means requiring an optical path between transmitter and receiver. Absent fibre or waveguides, IR telemetry is highly directional and limits a system to a single transmitter operating at a time in a direction. The directional nature of IR telemetry requires substantial alignment for optical communication.
Until recently, IR telemetry has been limited to low frequency communications. At low frequencies, it is difficult to multiplex channels, as a serial link requires higher frequencies than a true multi-channel implementation. Unfortunately, as noted above, IR telemetry is not suited to true multi-channel communications. The advent of high speed IR circuits may allow for channel multiplexing using a known technique such as time division multiplexing (TDM); however, this does not overcome previously mentioned shortcomings of IR.
OBJECT OF THE INVENTION
Thus in an attempt to overcome these and other limitations of the prior art it is an object of the present invention to provide a TET having multiple coils for implanting at multiple locations within a patient. Each coil receives a portion of transmitted energy and thereby results in exposure of tissue at each location to electromagnetic fields of lower intensity than result from use of a single pair of coils.
SUMMARY OF THE INVENTION
In a first broad aspect, the invention seeks to provide for a transcutaneous energy transfer device for coupling with a plurality of second coils. The device includes a plurality of first coils, each first coil for performing at least one of transmitting power to and receiving power from a coil from the plurality of second coils; and, a circuit, coupled to each coil from the plurality of coils for performing one of providing power to each coil of the plurality of first coils, the power provided for transmission therefrom, and receiving and combining power from each coil of the plurality of first coils. In an embodiment, the device also includes a plurality of second coils, each coil for transmitting power to a first coil; and a second circuit, coupled to each of the second coils for providing power to each of the second coils, the power provided for transmission from the second coils.
In accordance with the invention there is provided a transcutaneous energy transfer device for coupling with a second coil. The device includes a plurality of first coils, each first coil for performing at least one of transmitting power to and receiving power from the second coil; and a circuit, coupled to each coil from the plurality of coils for performing one of providing power to each coil of the plurality of first coils, the power provided for transmission therefrom, and receiving and combining power from each coil of the plurality of first coils. In an embodiment the plurality of first coils are for receiving power; wherein the circuit is for receiving power from each coil of the plurality of first coils and for combining power from each coil of the plurality of first coils; and, wherein the plurality of first coils are for implanting within a person. In another embodiment the device also includes a plurality of first coils, each first coil for implantation beneath the skin of a patient, the coils for receiving energy in the form of electromagnetic energy transmitted from outside the patient; a plurality of second coils for transmitting power received by the second coils in the form of electromagnetic radiation; a driver circuit for providing power to the second coils; and a circuit for combining the received energy received by the first coils and for providing power to an implanted device.
In accordance with another aspect of the invention, there is provided a method of providing power from an external circuit having a plurality of primary coils to an implanted circuit having a plurality of implanted secondary coils. The method comprises the steps of:
determining an amount of power to provide to the implanted circuit;
dividing the amount of power into a number of portions;
supplying sufficient power to each of a number of the primary coils to result in reception of a portion of the power at each of a number of the implanted secondary coils, the portions received at each of the implanted secondary coils forming the determined amount of power when combined.
In accordance with another embodiment of the invention, there is provided a transcutaneous energy transfer device. The device comprises a primary circuit comprising a plurality of primary coils coupled to at least a primary coil driver, a primary RF transceiver coupled to a plurality of the primary coils for transmitting and receiving RF signals, and primary signal filtering and extraction means for extracting information from the RF signal received by the primary RF transceiver; and a secondary circuit comprising a plurality of secondary coils, a secondary RF transceiver coupled to a plurality of the secondary coils, and secondary signal filtering and extraction means for extracting information from the RF signal received by the secondary RF transceiver.
BRIEF DESCRIPTION OF THE DRAWINGS
Exemplary embodiments of the invention, will now be described in conjunction with th e following drawings, in which:
FIG. 1 is a simplified diagram of a Baxter Pharmaceutical® Pump;
FIG. 2 is a circuit diagram of a TET according to the prior art;
FIG. 3 is a block diagram of an integrated voltage control and autotuning circuit implemented in an FPGA;
FIG. 4 is a partial circuit diagram of an RF telemetry system according to the present invention;
FIG. 5 is a partial circuit diagram of an alternative RF telemetry system according to the present invention;
FIG. 6a is a simplified diagram of a plurality of embedded coils according to the invention and associated circuitry; and
FIG. 6b is a simplified diagram of a plurality of embedded coils according to another embodiment of the invention and associated circuitry; and
FIG. 7 is a simplified diagram of a transcutaneous energy transfer device according to the invention wherein coils are implanted at many locations within a patient.
DETAILED DESCRIPTION OF THE INVENTION
Referring to FIG. 1, a Baxter Pharmaceutical® Pump is shown. The heart assist device operates to pump blood within a body. A solenoid 1 separates two levers 2. At an opposite end, the levers 2 are connected to compression means in the form of plates 4 that push against a sack 3. The compression of the sack 3 results in a pumping action. A fulcrum 5 is shown in order to clarify the motion of the levers 2.
This pumping action requires that the solenoid 1 receive adequate power. The solenoid 1 is provided power in an alternating fashion. Power is only provided while the solenoid 1 exerts force on the levers 2. Alternatively, power is provided all the time and the device converts the power signal into an alternating power signal. The conversion can be accomplished using energy storage and discharge means. Once the sack 3 is compressed, the solenoid must be turned off to allow the sack 3 to fill with fluid. Further, the solenoid 1 draws little power except when compressing the sack 3. Even during compression, power requirements vary throughout a stroke. The operation is well documented in the prior art.
The operation of the pump and similar devices draws energy inconsistently. As the load increases, voltage in the power supply is affected as is drive current. Increasing power supply voltage may result in voltage spikes when the load is removed. These power spikes are capable of damaging some devices. An approach to preventing this problem is to include voltage regulation means within each device to protect against power surges and voltage spikes. Prior art advances have addressed issues of power delivery and circuit tuning. Methods are known wherein voltage is regulated through a feed back loop or through autotuning.
Referring to FIG. 2, a TET device, known in the prior art, is shown. The device comprises a transformer designed to induce AC current in a subcutaneous winding for transformation to DC voltage for use in powering a medical device. Alternatively, the induced AC current is used to power a medical device. AC current is induced in L2, the secondary winding which may be, for instance, a torus core, wound with Litzendraht wire implanted just beneath the surface of the skin S with electrical leads connected to a medical device. A similar primary winding L1 is located in alignment with the secondary winding, on the skin surface and exterior thereto.
Primary winding L1 is connected to a capacitor 11 that is connected to the negative of a DC input bus. As indicated in FIG. 2, winding L1 is also connected to a field effect transistor (FET) 10 controlled by FET driver 20. FET driver 20 receives inputs from voltage-controlled oscillator 21, soft start control 22 and low voltage shutdown 23 to produce an alternating or pulsing waveform.
Power transfer may be considered to take place in two phases, a storage phase and a resonant phase. During the storage phase, energy is stored in the primary coil using a FET to switch the coil directly across the DC input supply. The FET is selected for its very low "on" resistance to minimise conduction losses.
As shown in FIG. 2, the coil L2 is implanted under the skin S. The remainder of the circuit remains external to the skin. Voltage is induced in the coil L2 from the coil L1, said coil and driver circuitry therefor remaining external to the skin S. Skin is capable of suffering damage from exposure to electrical fields for prolonged periods of time. Therefore, in designing TET devices, it is very useful to limit the electrical field necessary to induce sufficient voltage to provide necessary power.
Unfortunately, prior art circuits and methods do not address the significant problem of tissue damage. As discussed above, tissue damage results from prolonged exposure to electromagnetic fields. It is believed that reducing the field strength below a threshold field strength greatly increases tissue life. A method and device are presented herein for reducing the field strength across a patient's skin.
Referring to FIG. 3, an integrated voltage control autotuning circuit implemented in an FPGA is shown. Measurements of internal voltage and internal load are supplied to the control circuit via a telemetry link with a subcutaneous circuit (shown in FIG. 4). Such telemetry links are known using IR transmission and RF transmission. Based on the supplied values, the control circuit assesses the voltage control needs and the coupling efficiency in order to maintain appropriate levels of energy for the medical device. The FPGA controls the DC to AC converter, in the form of a plurality of FET drivers 20 and a power control circuit 43 (shown in FIG. 4), based on these values and based on system knowledge or calibration values. The FET drivers 20 are also used to control frequency and duty cycle. The circuit within the FPGA may incorporate other aspects of the TET circuitry.
Since a TET system must operate over various conditions, it is preferable that a control circuit has information relating to current conditions in order to set the correct operating point. In order to effectively autotune the TET and control voltage one of two methods is required. A first method comprises feedback from the coils L2. This feedback along with a circuit designed to correct voltage and to tune the circuit based on the feedback allow for improved operation of the TET. Alternatively, a sufficiently large number of coils operating efficiently within narrow ranges are employed and, even absent feedback, provide a secure and efficient coupling to a plurality of internal coils. Of course, feedback also provides valuable information relating to the internal device, patient health, TET failure, battery failure when a battery is used, and so forth.
When feedback of measured values is used, the programmable circuit responds to the measured values. When two values are measured in the form of load current and voltage, the measured values are low, normal, or high resulting in 9 possible combinations for each coil L2 from the plurality of coils L2. In this embodiment, phase is corrected using phase correction circuitry independent of the programmable circuit. For each of the 9 possible combinations the programmable circuit responds. The response may, for example, drift values toward an acceptable range. When measured load of a particular coil L2 increases, induced current is increased to maintain induced voltage substantially constant. When measured voltage increases, induced voltage is lowered to maintain induced voltage substantially constant. This effectively improves operation of the TET and prevents surges that can damage implanted devices. Further, since a plurality of coils are used to transmit and receive power across the skin, the skin at each coil location receives a fraction of the electromagnetic field strength required when using a single pair of coils, as taught in the prior art.
Alternatively, a single load measurement is used and the coils L2 are controlled in accordance therewith. In an embodiment, for example, each coil receives an equal fraction of the transmitted energy. In another embodiment, coils are driven as determined through calibration. According to yet another embodiment, each coil provides some feedback relating to coupling efficiency in order to maximise overall energy usage while maintaining electromagnetic radiation across the skin below the predetermined threshold.
Of course, phase correction circuitry may be implemented in association with the feedback information. Also, other corrective action may be implemented in order to maintain a desired coupling between external coils and implanted coils during operation of the TET device.
Different embodiments of control systems for maintaining sufficient power levels in the implanted circuit include the following features: a feedback loop for responding to current and past measured values; calibration of the circuitry to function with a specific implanted device; and/or calibration undertaken during an initial period of use, and an ongoing estimation of tissue damage due to electromagnetic field strengths and overall exposure times. A calibrated programmable circuit allows for corrective actions in anticipation of change. The system, for example, includes storage means for storing past sequences of measured values that were controlled inadequately. When these patterns occur, the programmable circuit responds differently than in previous attempts (within acceptable parameters) to better address the measured values. Estimation of tissue damage permits control of multiple external coils in an attempt to minimise overall tissue damage. For example, during a period of high demand, most but not all coils are driven to a higher than acceptable level. Once demand is reduced, those coils which were not driven above acceptable levels, are provided with a greater proportion of the energy to provide time for the tissue exposed to higher than acceptable levels of energy to recover from the exposure. Also, when coupling efficiency is reduced in a particular coil, decisions regarding which coil(s) will transfer that energy are related to the estimates of potential tissue damage.
Low internal voltage is caused by poor coupling or by high internal load. Providing both voltage and load from the internal coil to the external control circuit thereby allows for assessment of cause and appropriate control response. Of course, other feedback is also useful. For example, feedback relating to measured tissue damage, device operation, battery power level when a battery is used, coupling efficiencies, and so forth are useful with a multiple implanted coil implementation of a TET device.
Further, the use of multiple implanted coils has other advantages. Increased reliability occurs when each coil is capable of providing a large fraction of the necessary power or when there is a large number of coils. An external circuit failure has limited effect when many external circuits provide power to the implanted device. This is even more so when feedback indicates such a failure allowing for corrective action. Movement or misalignment of an energy source results in an indication of misalignment. This indication results in reduced power to that misaligned coil pair and increased power to other, better aligned pairs.
Turning to FIG. 4, a block diagram of a TET system according to an embodiment of the present invention and incorporating the programmable circuit of FIG. 3 is shown. The programmable circuit 40 in the form of an FPGA drives a plurality of FET drivers 20 and a power control circuits 43. The FET drivers 20 switch transistors 10 to drive the primary coils L1 in an alternating fashion. The power control circuits 43 control current and voltage provided to the coils L1 when switch transistors 10 are switched "on." The programmable circuit 40 receives inputs comprising timing in the form of a clock, power in the form of a voltage input, and monitored values received from at least a subcutaneous circuit via a telemetry link. The control functions within the programmable circuit 40 are dependent upon the received signals. Though a telemetry link in the form of an RF telemetry link is shown in FIG. 4, with the programmable circuit 40 any telemetry link providing a capability to transmit or receive all necessary monitored information will work. It is, however, preferable to use a true multi-channel communications means according to the present invention.
The RF transceiver 46 receives a signal via an antenna means 48 in the form of an RF antenna tuned to a predetermined frequency. Alternatively, the antenna means forms an integral part of the primary coil L1 (shown in FIG. 5). The received RF signal (at the RF transceiver 46) is filtered to reduce noise and remove unnecessary signals. Alternatively, this step is performed in the channel multi-band encoder/decoder 50. It is then decoded into individual channels or individual monitored values.
The channel structure of the information incorporates a channel for control information and a plurality of channels for monitored information. Control information is transmitted from the external circuit to the subcutaneous circuit. The subcutaneous circuit transmits diagnostic indicators in the form of bearing condition, blood sack shape, and device failure to the external circuit. Alternatively, the internal circuit sends control signals as well as diagnostic signals to the external circuit. In order to send a plurality of monitored values via a single channel, a method such as time division multiplexing (TDM) is employed. Using TDM, each value is assigned a time slot that repeats every frame. Within each frame a plurality of time slots each contains a value indicative of a measured or monitored characteristic. In each frame, the order of the plurality of channels is the same and, therefore, a value for each monitored characteristic is obtained by sampling the channel for that characteristic. Alternatively, when implanted coils are located a sufficient distance one from another, each coil transmits a single channel of information. Of course, duplication of transmitted information by transmitting same information from several implanted coils improves system robustness. Alternatively, a separate transceiver is used for transmitting information.
An example will demonstrate TDM. When 8 channels are within each frame, any value can be sampled based on the frame's frequency. Commonly, a frame pulse or a frame indicator signal are incorporated in order to align a transmitter and a receiver. From a frame's beginning a first channel value is sampled. From a frame's beginning+Δt(n/8 of a frame's period) an nth channel is sampled. In this way, a plurality of channels are transmitted across a single physical channel using serial communications. It is preferable to maintain at least some channels for security information to ensure that the telemetry link is between predetermined circuits. This is to minimise effects of stray signals.
A subcutaneous circuit comprises secondary coils L2 similar to the primary coils L1. An antenna 68 is disposed near the secondary coils L2 and in co-operation with an RF transceiver 66 sends monitored signals to the external circuit. Alternatively, monitored signals and control signals are transmitted. Alternatively, the secondary coils L2 also act as antennas. As with the external received and transmitted signals, noise is present in the subcutaneous received and transmitted signals in the form of white noise and cross talk from the power signal. A channel multi-band encoder/decoder 60 filters the noise and extracts desired signals. The channel multi-band encoder/decoder 60 also encodes monitored values to form appropriate RF signals in order to improve transmission effectiveness. Means such as forward error correction or parity are employed to improve the accuracy of the received and decoded signals.
The cross talk induced in a received signal is significant. A TET transmits energy via a coil pair. The energy transferred is often over 50 watts. The RF telemetry signal required to communicate between subcutaneous and external circuits transmits at a power level of several milliwatts. It is therefore important to shield circuitry (both external and subcutaneous) to ensure that once filtered, cross talk is not reintroduced. In a further embodiment, monitoring characteristics of at least some of the RF signals received, transmitting values in dependence upon the characteristics, and varying the RF signal parameters in the form of strength and frequency are implemented to improve telemetry robustness.
The channel multi-band encoder/decoder 60 receives information to encode for transmission from the monitoring means 64. The monitoring means for voltage and current form part of the AC to DC converter circuit when one exists. Alternatively, separate monitoring means are implemented. Of course, monitoring means are implemented to monitor any characteristic desirable in the subcutaneous circuit and in the implanted medical device.
In association with the improved power coupling control mechanism described herein, the RF telemetry system allows for a sufficient number of characteristics such as phase, voltage, drive current, bearing wear, battery status, and other non-essential characteristics such as blood flow, or muscle contraction. Each said characteristic is monitored internal to a body and transmitted via RF telemetry to an external control and monitoring circuit. Alternatively, external monitoring is also performed to indicate power signal voltage, communications signal strength, etc. and transmit monitored values via RF telemetry to a subcutaneous circuit. The use of RF telemetry, allows for each monitored characteristic to occupy a single channel or alternatively, for multiplexing a plurality of characteristics onto a single channel using a known method such as TDM.
Using RF telemetry, it is preferable to maintain a security ID or another form of transmitter verification to prevent effects of stray signals and to limit circuit response to signals originating from an appropriate transmitter.
Referring to FIG. 5, another embodiment wherein same coils act as transceivers of energy and information is shown. Here, a second antenna for transmitting information is not necessary.
Referring to FIG. 6a, an embodiment of the invention is shown using fewer external coils than internal coils. When coupling efficiency is of significant concern, energy levels are desired to be low, and the external coil(s) move as is currently the case, it is advantageous to couple a majority of energy from the external coil(s) to the internal coils.
As shown in FIG. 6b, a single external coil is disposed in close proximity to a patient. Implanted beneath the patient's skin is a plurality of secondary coils. The secondary coils are implanted in a pattern determined based on common types of movement of the external coil. For example, when the external coil is subject to movement in only one direction (Shown with arrows in FIG. 6b), coils are stacked as shown. The result is that movement that would have resulted in a significant loss of coupling efficiency, now results in a coupling with a different secondary coil. Coupling efficiency is maintained. Even during the transition, coupling efficiency is improved because coupling occurs with each of two secondary coils and, thereby, allows for more of the transmitted energy to be received by the implanted coils.
The internal coils are connected to a summing circuit where energy received is combined to form a single power signal. With the embodiment of FIG. 6a, further advantages exist in that a same internal coil couples with one external coil or another depending on the direction in which the external circuit has been moved. Obviously, allowing the external circuit to move relative to the internal circuit presents advantages in the form of increased patient comfort
Referring to FIG. 7, an embodiment is shown wherein the implanted coils L2 are disposed at many locations within the patient 70. This permits significant flexibility in terms of apparel and also provides for a large amount of circuit redundancy. Redundancy helps improve reliability. Some of the coil pairs L1, L2 shown may be replaced with multiple coil couplings shown in FIG. 6a. Each pair acts to independently transmit energy across tissue. The control circuitry acts to direct appropriate amounts of energy to each coil so as to reduce tissue damage while ensuring adequate energy for implanted device operation. Of course an absence of an external coil is not catastrophic when using a TET system according to the present invention.
According to an embodiment, exposure monitoring is performed for tissue exposed to electromagnetic radiation. The monitoring produces data that is stored as historical exposure data. Coils are provided with power in order to minimise potential damage based on historical exposure data, medical data provided through checkups of exposed regions, and required energy transmission levels. Using such a system, an adaptive approach that is capable of being customised to a particular user is provided wherein medical information provided during check-ups is then used to evaluate the significance of the historical exposure data and therefore allow for reduced overall tissue damage.
Numerous other embodiments may be envisaged without departing from the spirit and scope of the invention.
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In the design of transcutaneous energy transfer devices, variation in spacing between coils results in energy transfer efficiency changes. These changes may have significant effect on a system. It is proposed to provide a plurality of implanted coils for receiving energy simultaneously. Preferably, a plurality of coil pairs is used for transferring energy simultaneously. Also, a feedback system for use in a multiple coil system is disclosed.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application No. 61/591,432 filed on Jan. 27, 2012, and International Patent Application No. PCT/US2013/023085, filed on Jan. 25, 2013, both of which are hereby incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to a method and apparatus for the treatment of organic sludges and more particularly to a process for recovery of titanium dioxide and other inorganic materials from paint overspray or scrap paint in a sufficiently pure form so that it may be reused in the formulation and manufacture of new paint.
[0004] 2. Reference to Related Art
[0005] Usually, paint comprises three main components—pigments, binders, and solvents. Pigments include titanium dioxide, which is used to provide opacity, and small amounts of other compounds, both organic and inorganic, which create the color. The binders consist of various polymers and are used to attach the paint to the surface being painted and to hold the pigments in place. The solvents are the fluids, water or other chemicals, which act as a carrier to allow the paint to be sprayed, brushed or otherwise distributed over the surface to be painted. The solvents usually evaporate after the paint is dried to leave a hard dry surface.
[0006] When products such as appliances, furniture, automobile bodies and other manufactured goods are painted, the paint is usually applied using a spray applicator. This has the advantage of applying a uniform smooth layer of paint over the full surface of the part being sprayed. At the same time, an overspray is created that misses the part. The overspray is captured in a water curtain creating an aqueous sludge, which is most often gray in color as it is a mixture of a variety of paint colors. It contains a high percentage of titanium dioxide which can be reclaimed from the sludge and sold to the paint manufacturer to be used in paint formulations as a raw ingredient replacement for the virgin titanium dioxide.
[0007] Over the years, several patents have been published related to the recycling of paint sludge into a usable raw material. U.S. Pat. No. 5,543,367 issued Aug. 6, 1996 to Chaitanya K. Narula et al., discloses a process for decomposing dried paint sludge to recover the organic and inorganic components of the paint sludge in the form of gaseous, liquid, and composite materials. The process comprises drying the paint sludge to remove water and organic solvents, pyrolizing the dried paint sludge in an inert atmosphere in an elevated temperature of up to about 600° C. to form gaseous and liquid decomposition materials and a solid residue. The process further comprises collecting the gaseous and liquid decomposition materials and subjecting the solid residue to sintering at an elevated temperate of about 900° to 1300° C. in an atmosphere of nitrogen, argon or ammonia to convert the solid residue to composite materials comprising barium titanate and titanium compounds such as titanium dioxide, titanium nitride, and titanium carbide that may be used as reinforcing fillers. The gaseous and liquid materials may be further pyrolyzed to carbon materials.
[0008] U.S. Pat. No. 5,087,375 issued Feb. 11, 1992 to Peter Weinwurm discloses a method for handling, treating, heating, and incinerating on-site liquid waste, sewage, sludge, cakes or solid waste. The primary treatment process utilizes a 0.1-50% of plastic clay and may include separation, absorption, precipitation, neutralization, sedimentation, flocculation, coagulation, filtration or dewatering. The residue remaining after the primary treatment is mixed with additional clay or silicates and a suitable absorbent for either organic or inorganic, liquid material, to form a solid mixture of approximately 5-50% clay or silicates and 0.1-10% absorbent. The solidified mixture is formed into granules or other shapes having large surface area. The stable, solid granules are transferred to a conveyorized oven, dried and pyrolized or fired. Resulting organic gases may be condensed to oil, or exhaust gases may be vented into a secondary incineration unit. The resulting product is composed of stable granules, detoxified of organic waste and with all inorganic waste converted into silicate form in which the sludge is mixed with a reagent powder, heated at 350° C. for a sufficient amount of time to yield a residue powder and distilled solvents. The solid residue is only suitable for use as filler in cement or as a reagent to create additional solid residue.
[0009] U.S. Pat. No. 5,490,907 issued Feb. 13, 1996 to Peter Weinwurm et al. and related to the '375 patent above discusses a method for the separation and recovery of volatiles from a sludge containing liquid solvents (about 1 to 80% by weight) and solids (20 to 99% by weight), in which said sludge is fed with a reagent powder material in an amount effective to form a mixture having a high surface area to a distillation vessel. The mixture is heated to a temperature up to about 350° C. While the mixture is advanced through the vessel for a time sufficient to distil a sufficient portion of the solvents to yield a solid residue powder, distilled solvents are condensed, and the solid residue powder recovered. The vessel preferably is a mechanical fluidized bed distillation vessel and the mixture is fluidized while being heated therein under a partial vacuum in a non-oxidizing atmosphere. The effective amount of reagent powder material includes about 5 to 70 wt % of the reagent powder material. The solid residue is also suitable only for use as filler in cement or as a reagent to create additional solid residue.
SUMMARY OF THE INVENTION
[0010] There is a need for a process, in which the gasses can be used directly from the process or the solid residue can be used to make additional paint.
[0011] The process of the invention converts the organic portion of the paint sludge into a synthetic natural gas that can be supplied directly to a kiln or other heat source to replace coal, oil, natural gas or other fuel. Advantageously, it requires no further treatment because the exhaust from the kiln passes through a scrubber and will remove any unacceptable contaminant. Further in accordance to the process of the invention, the inorganic portion of the sludge is converted into a powder of sufficient purity to be used as a raw material to replace titanium oxide and other pigments in the manufacture of paint.
[0012] The method of processing paint sludge according to the present invention provides supplying measured portions of the sludge from a source of sludge into a heating chamber, and subjecting the sludge to pyrolysis in the heating chamber at the temperature of about 1500° F., whereby the sludge is disintegrated into organic and inorganic portions. Then, the organic portion in the form of syngas is drawn from the heating chamber, and the syngas is cooled and pressurized, and thus becomes ready for directing to a consumer, such as kiln.
[0013] Alternatively, or concurrently with processing the organic portion, the inorganic portion in the form of ash is directed after the pyrolysis from the heating chamber into a calciner, and is heated there at about 1500° F. for a period of time from several minutes to several hours in a controlled presence of oxygen in the calciner to maintain reducing condition therein, and after cooling the residue becomes ready for the reuse in paint manufacturing.
[0014] The measured portions of sludge can be prepared by providing valves before the heating chamber. The valves work in a synchronized cycling mode so that a portion of sludge from the source is allowed between the valves and then into the heating chamber.
[0015] A non-reacting gas is injected between the valves to purge oxygen out and prevent syngas from coming in.
[0016] The non-reacting gas is injected into the heating chamber during the pyrolysis to maintain oxygen-free environment.
[0017] The sludge is preferably moved along the heating chamber during the pyrolysis.
[0018] The time of pyrolysis is selected between 15 minutes and several hours depending on quality of the sludge and heating chamber dimensions.
[0019] Drawing the syngas from the heating chamber can be performed by creating suction pressure outside the vent.
[0020] It is preferable to pass the syngas through a water bath before pressurizing to get rid of contaminants from the syngas.
[0021] The ash in the step is directed from the heating chamber into the calciner in a measured manner which is secured by providing valves. They work in a synchronized cycling mode so that a portion of ash from the heating chamber is allowed between the valves and then onto a conveyor to the calciner, the non-reacting gas being injected between the valves.
[0022] Cooling the residue after the calciner is performed in a cooling chamber in the presence of the non-reacting gas.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] These and other features and advantages of the present invention will be clearly understood from the ensuing description and the only accompanying drawing where a schematic flow diagram illustrates the implementation of the method of the invention is presented.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0024] With reference to the flow diagram of the drawing showing a unit 10 for treating paint sludge, the whole process of treating is controlled by a computer (not shown). The paint sludge represented by 12 is being fed into a hopper 14 . The sludge does not need to be pre-dried. Going from the hopper 14 is a pipe 15 with three valves. A first gate valve 16 in its open position allows a measured amount of sludge to pass through and drop onto a second gate valve 18 , which is closed. By way of example, the measured amount of paint sludge can be about 1 cu ft (30-40 lbs). The gate valve 18 allows the space between the valves 16 and 18 to be pressurized with nitrogen and prevent oxygen from leaking in and displacement of reactor gas (syngas) into the feed hopper 14 . For the purpose of this application, terms “nitrogen,” “inert gas,” and “non-reacting gas” are interchangeable.
[0025] Further, the first gate valve 16 closes, and the second gate valve 18 opens allowing the measured amount of sludge to drop onto a third gate valve 20 , which is closed. The second gate valve 18 closes, and a small amount of nitrogen is injected (not shown) into the space between the valves 18 and 20 to maintain flow upwards during cycling—to purge the oxygen from the space, and downward—to displace syngas. The gate valve 20 then opens to allow the sludge to drop from the pipe 15 into a round heating chamber 22 . Thus, the sludge is being fed incrementally as the valves 16 , 18 , and 20 cycle. The heating chamber 22 , where the sludge is separated into organic and inorganic portions, is a horizontal cylinder having the diameter and length sufficient to allow a desired amount of sludge to be treated during a desired period of time. The chamber 22 is heated up to 1,500° F. For heating, a gas fire burner placed between an insulated box (not shown), which the chamber 22 is encapsulated in, and the tube of the chamber can, for example, be used.
[0026] Within the heating chamber 22 , a screw conveyor 24 carries the sludge forward (from left to right on the drawing) at a predetermine rate towards the opposite (discharge) end of the chamber 22 . The conveyor is a conventional screw/auger type conveyor. By way of example, the rate of carrying the sludge is about 1 ft/min in the unit being constructed. Then, the throughput is expected to be at the level of about 3000 lb/hr, but in practice it is scalable and is based on the market demands. The rates are defined by the size and speed of the unit discussed below. The actual rate achieved will be also dependent on qualities of the feed material, and can vary among the sources of material. The conveyor 24 is used to carry the sludge through the chamber 22 because it allows filling most of the chamber space thus not requiring large amounts of nitrogen to maintain an oxygen free environment. The screw conveyor 24 and an inner surface of the heating chamber 22 may be chrome plated to facilitate material flow and prevent the surface from reacting with, or being corroded by, the material being processed. The screw diameter and length of the chamber can vary, respectively, from 5″ in diameter and 10′ in length, as in a pilot system, up to, respectively, 36″ and 20′÷30′ in a larger scale unit. Ultimately, the practical limit will be the size of components that are manageable for assembly and maintenance. The length, diameter, screw pitch, and rotation speed are all variables determining the residence time of material in the reactor vessel (larger vessel and the same speed will result in longer residence times). It is believed that the appropriate space (difference between the diameters of the conveyor and the chamber) is about 3″÷4″. A smaller space can restrict material flow. A larger one may impact quality. By and large, the optimum is dependent on the nature of the raw material used.
[0027] Depending on quality of the feed material, its residence time within the chamber 22 can vary from 15 minutes up to several hours. It is the fraction of water and organics in the feed material that will determine the time required to first dry and then pyrolyze the material—those (water content and volatiles content) are the primary quality attributes of the feed that determine required residence times. As the sludge is heated in what is effectively a pyrolysis step—a conversion of solids to gases through increasing the material temperature in the absence of oxygen, -the organic portion of the sludge converts to syngas vented from the chamber 22 through a vent 26 . Moderate amount of non-reacting gas introduced into the chamber 22 allow not separating it from the syngas. In this way, the syngas can be used without further treatment, thus increasing its value. A slight vacuum (suction pressure) created by a fan 28 draws the syngas from the chamber through a water jacketed pipe 30 to cool the gas, through a water bath 32 to scrub contaminants from the gas, through a secondary water bath 34 , through the fan 28 into a storage tank 36 . A compressor 38 pulls the accumulated gas from the storage tank 36 and compresses the gas to about 50 psi in a second storage tank 40 . By means of pressure regulated valves (not shown) the compressed syngas is then piped directly to a kiln or other combustion chamber (not shown). There, the syngas is used without further treatment because the kiln or combustion chamber are conventionally equipped with scrubbers and air cleaners to remove any contaminants that may remain after combustion. The process according to the present invention can be potentially self-powered with the syngas.
[0028] The inorganic portion of the sludge (in the form of ash, which can comprise metals sought for reusing) is discharged from the bottom of the heating chamber 22 through a first isolation valve 42 onto a second isolation valve 44 . The isolation valve 44 opens, and the ash drops therethrough in a chamber 46 filled with a non-interacting gas onto a third isolation valve 48 . The isolation valve 44 is then closed. The isolation valve 48 is then opened to allow the ash to drop onto a conveyor 50 . The conveyor 50 carries the ash into a calciner 52 . The ash is heated up to 1,500° F., and oxygen is introduced (not shown) into the calciner 52 at a controlled rate to maintain reducing conditions in the calciner and allow any carbon residue on the ash to be oxidized and removed from the ash. The residual matter is discharged through a fourth isolation valve 54 into a cooling chamber 56 . The valve 54 is closed, and a non-interacting gas is used in the cooling chamber 56 to maintain a controlled, reducing environment. After the matter is cooled, a sixth isolation valve 58 is opened and the inorganic residue, which can be recycled in a paint manufacturing process, is discharged into a container 60 for further shipment to a customer.
[0029] Significant differences of the method of the present invention from the prior art methods disclosed in the above-discussed patents include:
1. No reagent material is used in the process of the present invention. The presence of reagent reduces the value and potential use of the ash. 2. The screw conveyor is used in the present invention to eliminate most, if not all, void space in the heating chamber. This minimizes the amount of inert gas used in the process. If the volume of inert gas mixed with the synthetic natural gas is significant, it must be removed from the synthetic natural gas before the syngas can be used. Keeping the inert gas to small amounts allows using the syngas without further treatment, thus increasing the value of the natural gas. 3. The syngas produced according to the present invention is piped directly to a kiln or other combustion chamber which have scrubbers and air treatment systems in place, thus eliminating the need for significant cleaning of the syngas before it can be used. In case of a lime kiln, the syngas would replace coal and provide a cleaner fuel source. 4. According to the present method, the sludge does not need to be pre-dried. 5. According to the present method, the ash can be reused in the manufacture of paint whereas in prior art patents the ash is only suitable as a filler material. 6. Used in the present invention is a two-prong operation in which the gas is bled off as the ash passes through a secondary process in the presence of a controlled amount of oxygen which causes any carbon residue to be oxidized without oxidizing the inorganic ash.
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In a method of processing paint sludge, measured portions of the sludge are supplied into a heating chamber for pyrolysis at about 1500° F. to disintegrate into organic and inorganic portions, the organic portion in the form of syngas is then drawn out, cooled, and pressurized to be used in kilns or combustion chambers, whereas the inorganic portion in the form of ash is directed to a calciner, where it is heated at about 1500° F. in a controlled presence of oxygen and cooled to have it ready for the reuse in paint manufacturing.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for the preparation of aldehydes and ketones
2. The Prior Art
Aldehydes and ketones are widely used in organic chemistry. For example, they are important precursors in the synthesis of heterocycles, or perfumes and dyestuffs.
A variety of processes are known for the preparation of aldehydes and ketones. For example, the formyl and the acyl group are successfully introduced directly into aromatic systems via electrophilic substitution reactions, which, however, are limited by the substitution rules. Aromatic ketones can also be synthesized via organometallic reactions. A disadvantage includes the necessity of using an anhydrous reaction medium. Another disadvantage is the use of toxic chemicals such as phosphorus oxychloride, carbon monoxide, zinc cyanide, mercury organyls and cadmium organyls.
Aldehydes and ketones may also be synthesized via oxidation reactions. An overview is given in the literature reviewed in Houben-Weyl, Vol. E3, p. 230 et seq., 1983, and Vol. 7/2a, p. 688 et seq. Customary oxidants are selenium dioxide, chromium trioxide, cerium(IV) ammonium nitrate in perchloric acid/nitric acid or manganese dioxide in concentrated sulfuric acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or iodine in DMSO. These oxidants, however, are also not very suitable for larger-scale syntheses due to their toxicity, the high costs or difficult handling. Moreover, most syntheses are complicated and yield the desired aldehyde only in moderate yield. In accordance with Org. Synth. Coll. Vol. IV, 1961, p. 31, 4-aminobenzaldehyde can be synthesized from nitrotoluene with the aid of polysulfide. Purification of the reaction product, which has a tendency to polymerize, is difficult and must be carried out rapidly, so that this process is unsuitable for larger amounts of substance.
When carrying out the oxidation with oxygen with addition of catalysts, not only are the desired aldehydes formed, but in most cases also the corresponding carboxylic acids (see Houben-Weyl, Vol. E3, p. 234 et seq., 1983). If this process is carried out with addition of N-hydroxyphthalimide and Co(II) or Co(III) compounds, even the starting material is fully oxidized to give the carboxylic acid (Ishii et al., J. Org. Chem. 1996, 61, 4520). Aromatic ketones are formed from alkylbenzenes with the aid of N-hydroxyphthalimide and acetaldehyde/oxygen in nonaqueous medium (Einhorn et al. in Chem. Commun. 1997, 447). The formation of aromatic aldehydes from the corresponding methyl aromatics with the aid of the enzyme laccase and ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) was described by Potthast in J. Org. Chem. 1995, 60, 4320. However, it was impossible to reproduce these results in independent experiments. Moreover, the laccase mentioned in the publication, by Mercian, which has an activity of 1.1×10 4 (IU/ml, based on the conversion of 4-hydroxymandelic acid as substrate), is not available. When attempting to reproduce the results, an available product, namely Mercian laccase with an activity of approx. 95 IU/ml, was employed at 100-fold concentration. A difficulty is that such high amounts of enzyme would completely exclude an applicability of the method for preparative purposes. Under these conditions, not even traces of an oxidation of 4-nitrotoluene was observed. When 3,4-dimethoxytoluene was used in the conversion, only 0.3% of 3,4-dimethoxybenzaldehyde were detected. Synthetic methods using ABTS are generally limited by the price of the compound, which is high.
There is therefore a demand for an inexpensive process which allows even sensitive aldehydes to be synthesized on a large scale. In particular, there is a need for a process in which water can be used as reaction medium.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of vinyl, alkynyl, aryl or heteroaryl aldehydes or vinyl, alkynyl, aryl or heteroaryl ketones from vinyl-, alkynyl-, aryl- and heteroarylmethyl and -methylene compounds with the aid of a mediator and an oxidant, wherein the mediator is selected from the group of the aliphatic, heterocyclic or aromatic NO, NOH or ##STR1## containing compounds.
The vinyl, alkynyl, aryl and heteroaryl aldehydes and vinyl, alkynyl, aryl and heteroaryl ketones are preferably compounds of the formula 1, and the vinyl-, alkynyl-, aryl- and heteroarylmethyl and -methylene compounds are preferably compounds of the formula 2 ##STR2## where Y 1 and Y 2 can be identical or different and are radicals having up to 20 C atoms and up to 6 rings and at least one of the radicals Y 1 or Y 2 is vinyl, alkynyl, aryl or heteroaryl, and Y 1 and Y 2 may also be part of a ring system.
Y 1 is preferably an aromatic or heteroaromatic ring or ring system having up to 6 rings and up to 20 C atoms, whose ring members can be replaced by O, S or N atoms, or an anthraquinonyl radical, it being possible for the aromatic or heteroaromatic radical Y 1 to be mono- to hexasubstituted, it being possible for the substituents to be identical or different and to have the meaning of OH, a linear, branched or cyclic C 1 -C 12 -alkyl radical, it being possible for adjacent alkyl groups to form a 5-, 6- or 7-membered ring via a methylene group, or a linear or branched C 1 -C 12 -oxyalkyl or thioalkyl radical, it being possible for adjacent substituents to form a 5-, 6- or 7-membered ring via a methylene group, a H 2 N-- or a linear or branched C 1 -C 12 --N-alkylamino, a linear or branched C 1 -C 12 --N,N-dialkylamino group, NC--, O 2 N--, halogen, HOOC--, HO 3 S--, OHC--, H 2 N--COO--, H 2 N--CO--, H 2 N--CO--NH--, or a linear, branched or cyclic C 1 -C 12 --OCO--, C 1 -C 12 --COO--, C 1 -C 12 --CO--, C 1 -C 12 --NHCO--, C 1 -C 12 --NHCONH--, (C 1 -C 12 ) 2 NCO--, C 1 -C 12 --CONH-- group, or a linear or branched C 1 -C 12 --OSO 2 --, C 1 -C 12 --NH--SO 2 --, or (C 1 -C 12 ) 2 N--SO 2 -- group, or a phenyl, diphenylmethyl, phenyl-CH═CH--, phenyl-N═N--, phenyl-N═CH--, phenyl-CH═N--, phenoxy, phenyl-NH--, phenyl-O--CO--, phenyl-CO--, phenyl-NHCO--, phenyl-CONH--, phenyl-NHCONH--, phenyl-OSO 2 -- or phenyl-NH--SO 2 -- group whose phenyl radicals can be mono- to pentasubstituted, it being possible for the substituents to be identical or different and to have the meaning of OH, a linear, branched or cyclic C 1 -C 12 -alkyl radical, it being possible for adjacent alkyl groups to form a 5-, 6- or 7-membered ring via a methylene group, or of a linear or branched C 1 -C 12 -oxyalkyl or thioalkyl radical, it being possible for adjacent substituents to form a 5-, 6- or 7-membered ring via a methylene group, a H 2 N-- or a linear or branched C 1 -C 12 --N-alkylamino, a linear or branched C 1 -C 12 --N,N-dialkylamino group, NC--, O 2 N--, halogen, HOOC--, HO 3 S--, OHC--, H 2 N--COO--, H 2 N--CO--, H 2 N--CO--NH--, or a linear, branched or cyclic C 1 -C 12 --OCO--, C 1 -C 12 --COO--, C 1 -C 12 --CO--, C 1 -C 12 --NHCO--, C 1-C 12 --NHCONH--, (C 1 -C 12 ) 2 NCO--, C 1 -C 12 --CONH--, or of a linear or branched C 1 -C 12 --OSO 2 --, C 1 -C 12 --NH--SO 2 -- or (C 1-C 12 ) 2 N--SO 2 -- group, or of a phenyl, diphenylmethyl, phenyl-CH═CH--, phenyl-N═N--, phenyl-N═CH--, phenyl-CH═N--, phenoxy, phenyl-NH--, phenyl-O--CO--, phenyl-CO--, phenyl-NHCO--, phenyl-CONH--, phenyl-NHCONH--, phenyl-OSO 2 -- or phenyl-NH--SO 2 -- group or an optionally mono- to trisubstituted vinyl radical or optionally substituted ethynyl radical, in which the substituents can be identical or different and have the meaning of hydrogen, linear, branched or cyclic C 1 -C 12 -alkyl radical where one or more methylene groups can be replaced individually by CHOH, CO, O, S, NH or by a linear or branched C 1 -C 12 --N-alkylamine radical, or in which the vinyl group forms part of a ring or ring system, and Y 2 is hydrogen, linear, branched or cyclic C 1 -C 12 -alkyl radical where one or more methylene groups can be replaced individually by CHOH, CO, O, S, NH or by a linear or branched C 1 -C 12 --N-alkylamine radical, or an aromatic or heteroaromatic ring or ring system having up to 6 rings and up to 20 C atoms, whose ring members can be replaced by O, S or N atoms, or anthraquinonyl radical, or an optionally mono- to trisubstituted vinyl radical or optionally substituted ethynyl radical, in which the substituents can be identical or different and have the meaning of hydrogen, linear, branched or cyclic C 1 -C 12 -alkyl radical where one or more methylene groups can be replaced individually by CHOH, CO, O, S, NH or by a linear or branched C 1 -C 12 --N-alkylamine radical, or in which the vinyl group forms part of a ring or ring system.
Equally preferred are compounds in which the radicals Y 1 and Y 2 are linked via a methylene group or an ether group or via an amino group which is optionally substituted by a linear, branched or cyclic C 1 -C 12 -alkyl radical.
Especially preferably, Y 1 is a 5-, 6- or 7-membered aromatic or heteroaromatic ring which can be fused to one or two further aromatic rings and where one to four C atoms can be replaced by O, S or N atoms, or an anthraquinonyl radical, it being possible for y 1 to be mono- to tetrasubstituted, it being possible for the substituents to be identical or different and to have the meaning of OH, a linear, branched or cyclic C 1 -C 6 -alkyl radical, it being possible for adjacent alkyl groups to form a 5- or 6-membered ring via a methylene group, or a linear or branched C 1 -C 6 -oxyalkyl or -thioalkyl radical, it being possible for adjacent substituents to form a 5- or 6-membered ring via a methylene group, of a H 2 N--, or a linear or branched C 1 -C 6 --N-alkylamino, a linear or branched C 1 -C 3 --N,N-dialkylamino group, NC--, O 2 N--, halogen, HOOC--, HO 3 S--, OHC--, H 2 N--COO--, H 2 N--CO--, H 2 N--CO--NH--, or a linear, branched or cyclic C 1 -C 6 --OCO--, C 1 -C 6 --COO--, C 1 -C 6 --CO--, C 1 -C 6 --NHCO--, C 1 -C 6 --NHCONH--, (C 1 -C 6 ) 2 NCO--, C 1 -C 6 --CONH--, or of a linear or branched C 1 -C 6 --OSO 2 --, C 1 -C 6 --NH--SO 2 -- or (C 1 -C 3 ) 2 N--SO 2 -- group, or of a phenyl, diphenylmethyl, phenyl-CH═CH--, phenyl-N═N--, phenyl-N═CH--, phenyl-CH═N--, phenoxy, phenyl-NH--, phenyl-O--CO--, phenyl-CO--, phenyl-NHCO--, phenyl-CONH--, phenyl-NHCONH--, phenyl-OSO 2 -- or phenyl-NH--SO 2 -- group,
it being possible for the phenyl radicals to be mono- to trisubstituted, it being possible for the substituents to be identical or different and to have the meaning of OH, a linear, branched or cyclic C 1 -C 6 -alkyl radical, it being possible for adjacent alkyl groups to form a 5- or 6-membered ring via a methylene group, or a linear or branched C 1 -C 6 -oxyalkyl or -thioalkyl radical, it being possible for adjacent substituents to form a 5- or 6-membered ring via a methylene group, of a H 2 N--, or a linear or branched C 1 -C 6 --N-alkylamino, a linear or branched C 1 -C 3 --N,N-dialkylamino group, NC--, O 2 N--, halogen, HOOC--, HO 3 S--, OHC--, H 2 N--COO--, H 2 N--CO--, H 2 N--CO--NH--, or a linear, branched or cyclic C 1 -C 6 --OCO--, C 1 -C 6 --COO--, C 1 -C 6 --CO--, C 1 -C 6 --NHCO--, C 1 -C 6 --NHCONH--, (C 1 -C 6 ) 2 NCO--, C 1 -C 6 --CONH--, or of a linear or branched C 1 -C 6 --OSO 2 --, C 1 -C 6 --NH--SO 2 -- or (C 1 -C 3 ) 2 N--SO 2 -- group, or of a phenyl, diphenylmethyl, phenyl-CH═CH--, phenyl-N═N--, phenyl-N═CH--, phenyl-CH═N--, phenoxy, phenyl-NH--, phenyl-O--CO--, phenyl-CO--, phenyl-NHCO--, phenyl-CONH--, phenyl-NHCONH--, phenyl-OSO 2 -- or phenyl-NH--SO 2 -- group, or
an optionally mono- to trisubstituted vinyl radical or optionally substituted ethynyl radical, it being possible for the substituents to be identical or different and to be hydrogen or linear, branched, or cyclic C 1 -C 6 -alkyl radical where one or two methylene groups can be replaced individually by --CHOH, CO, O, S, NH or by a linear or branched C 1 -C 6 --N-alkylamine radical, or in which the vinyl group forms part of a 5- or 6-membered ring or of a ring system, and
Y 2 is hydrogen or linear, branched or cyclic C 1 -C 6 -alkyl radical where one or two methylene groups can be replaced individually by --CHOH, CO, O, S, NH or by a linear or branched C 1 -C 6 --N-alkylamine radical, or a 5-, 6- or 7-membered aromatic or heteroaromatic ring which can be fused to one or two further aromatic rings and where one to four C atoms can be replaced by O, S or N atoms, or an anthraquinonyl radical, or an optionally mono- to trisubstituted vinyl radical, or an optionally substituted ethynyl radical, it being possible for the substituents to be identical or different and to be hydrogen or linear, branched, or cyclic C 1 -C 6 -alkyl radical where one or two methylene groups can be replaced individually by --CHOH, CO, O, S, NH or by a linear or branched C 1 -C 6 --N-alkylamine radical, or in which the vinyl group forms part of a 5- or 6-membered ring or of a ring system.
Equally especially preferred are compounds where the radicals Y 1 and Y 2 are linked via a methylene group or an ether group or via an amino group which is optionally substituted by a linear, branched or cyclic C 1 -C 6 -alkyl radical.
Very especially preferably, Y 1 is phenyl, naphthyl, anthryl, phenanthryl, azulenyl, anthraquinonyl, furyl, pyrrolyl, thienyl, benzofuranyl, isobenzofuranyl, benzothiyl, isobenzothienyl, indolyl, isoindolyl, indolizinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, indazolyl, carbazolyl, benzotriazolyl, purinyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phenanthridinyl, acridinyl, 1,10-phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, it being possible for Y 1 to be mono- to trisubstituted, it being possible for the substituents to be identical or different and to have the meaning of OH, a linear C 1 -C 6 -alkyl radical, it being possible for adjacent alkyl groups to form a 5- or 6-membered ring via a methylene group, or of a linear C 1 -C 6 -oxyalkyl radical, it being possible for adjacent substituents to form a 5- or 6-membered ring via a methylene group, a H 2 N--, or a linear C 1 -C 6 --N-alkylamino, a linear C 1 -C 3 --N,N-dialkylamino group, NC--, O 2 N--, halogen, HOOC--, HO 3 S--, OHC--, H 2 N--COO--, H 2 N--CO--, H 2 N--CO--NH--, or a linear C 1 -C 4 --OCO--, C 1 -C 4 --COO--, C 1 -C 4 --CO--, C 1 -C 4 --NHCO--, (C 1 -C 4 ) 2 NCO--, C 1 -C 4 --CONH--, C 1 -C 4 --NHCONH--, or C 1 -C 4 --OSO 2 --, C 1 -C 4 --NH--SO 2 -- or (C 1 -C 3 ) 2 N--SO 2 -- group, or of a phenyl, diphenylmethyl, phenyl-CH═CH--, phenyl-N═N--, phenyl-N═CH--, phenyl-CH═N--, phenoxy, phenyl-NH--, phenyl-O--CO--, phenyl-CO--, phenyl-NHCO--, phenyl-CONH--, phenyl-NHCONH--, phenyl-OSO 2 -- or phenyl-NH--SO 2 -- group, it being possible for the phenyl radicals to be mono- to trisubstituted, it being possible for the substituents to be identical or different and to have the meaning of OH, a linear C 1 -C 6 alkyl radical, it being possible for adjacent alkyl groups to form a 5- or 6-membered ring via a methylene group, or of a linear C 1 -C 6 -oxyalkyl radical, it being possible for adjacent substituents to form a 5- or 6-membered ring via a methylene group, a H 2 N--, or a linear C 1 -C 6 --N-alkylamino, a linear C 1 -C 3 --N,N-dialkylamino group, NC--, O 2 N--, halogen, HOOC--, HO 3 S--, OHC--, H 2 N--COO--, H 2 N--CO--, H 2 N--CO--NH--, or a linear C 1 -C 4 --OCO--, C 1 -C 4 --COO--, C 1 -C 4 --CO--, C 1 -C 4 --NHCO--, (C 1-C 4 ) 2 NCO--, C 1-C 4 --CONH--, C 1 -C 4 --NHCONH--, or C 1 -C 4 --OSO 2 --, C 1 -C 4 --NH--SO 2 -- or (C 1 -C 3 ) 2 N--SO 2 -- group, or of a phenyl, diphenylmethyl, phenyl-CH═CH--, phenyl-N═N--, phenyl-N═CH--, phenyl-CH═N--, phenoxy, phenyl-NH--, phenyl-O--CO--, phenyl-CO--, phenyl-NHCO--, phenyl-CONH--, phenyl-NHCONH--, phenyl-OSO 2 -- or phenyl-NH--SO 2 -- group or an optionally mono- to trisubstituted vinyl radical, or optionally substituted ethynyl radical, in which the substituents can be identical or different and are hydrogen or linear C 1 -C 6 -alkyl radical where one or two methylene groups can be replaced individually by CHOH, CO, O, S, NH or by a linear or branched C 1 -C 6 --N-alkylamine radical, or in which the vinyl group forms part of a 5- or 6-membered ring or of a ring system, and Y 2 is hydrogen or a linear C 1 -C 6 -alkyl radical where one or two methylene groups can be replaced individually by CHOH, CO, O, S, NH or by a linear or branched C 1 -C 6 --N-alkylamine radical, or is phenyl, naphthyl, anthryl, phenanthryl, azulenyl, anthraquinonyl, furyl, pyrrolyl, thienyl, benzofuranyl, isobenzofuranyl, benzothiyl, isobenzothienyl, indolyl, isoindolyl, indolizinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, indazolyl, carbazolyl, benzotriazolyl, purinyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phenanthridinyl, acridinyl, 1,10-phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or an optionally mono- to trisubstituted vinyl radical, or optionally substituted ethynyl radical, in which the substituents can be identical or different and are hydrogen or linear C 1 -C 6 -alkyl radical where one or two methylene groups can be replaced individually by CHOH, CO, O, S, NH or by a linear or branched C 1 -C 6 --N-alkylamine radical, or in which the vinyl group forms part of a 5- or 6-membered ring or of a ring system.
Examples of such compounds are toluene, ethylbenzene, propylbenzene, ortho-, meta- and para-xylene, 3,4-dimethoxytoluene, 4-methylaniline, diphenylmethane, propene, 2-butene, 1-octene and 3-phenyl-1-propyne.
Equally very especially preferred are compounds in which the radicals Y 1 and Y 2 are linked via a methylene group or an ether group or via an amino group which is optionally substituted by a methyl, ethyl, n- or iso-propyl radical, the linkage resulting in 5- or 6-membered rings.
Examples are cyclohexene, indane, indene, 1,2,3,4-tetrahydronaphthalene, 6-methoxy-1,2,3,4-tetrahydronaphthalene, 9,10-dihydrophenanthrene, 3,4-dihydro-2H-pyrane, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline.
The mediator used is preferably at least one compound selected from the group of the aliphatic, cycloaliphatic, heterocyclic or aromatic compounds which contains at least one N-hydroxyl, oxime, nitroso, nitroxide or N-oxide function.
Examples of such compounds are the compounds of the formula I, II, III or IV, mentioned below, the compounds of the formulae II, III and IV being preferred and the compounds of the formulae III and IV being especially preferred.
Compounds of the general formula I are: ##STR3## where X is one of the following groups: (--N═N--), (--N═CR 4 --) p , (--CR 5 ═CR 6 ) p ##STR4## and p equals 1 or 2, it is being possible for the radicals R 1 to R 6 to be identical or different and independently of one another to represent one of the following groups: hydrogen, halogen, hydroxyl, formyl, carboxyl, and the salts and esters thereof, amino, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl, sulfono, esters and salts thereof, sulfamoyl, carbamoyl, phospho, phosphono, phosphonooxy and their salts and esters, and it furthermore being possible for the amino, carbamoyl and sulfamoyl groups of the radicals R 1 to R 6 to be unsubstituted or to be mono- or disubstituted by hydroxyl, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy,
and it being possible for the radicals R 2 and R 3 to form a joint group --A--, where --A-- represents one of the following groups:
(--CR 7 ═CR 8 --CR 9 ═CR 10 --) or (--CR 10 ═CR 9 --CR 8 ═CR 7 --).
The radicals R 7 to R 10 can be identical or different and independently of one another can represent one of the following groups: hydrogen, halogen, hydroxyl, formyl, carboxyl and the salts and esters thereof, amino, nitro, C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl sulfono, esters and salts thereof, sulfamoyl, carbamoyl, phospho, phosphono, phosphonooxy and their salts and esters, and it furthermore being possible for the amino, carbamoyl and sulfamoyl groups of the radicals R 7 to R 10 to be unsubstituted or to be mono- or disubstituted by hydroxyl, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, and it being possible for the C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl or aryl groups of the radicals R 7 to R 10 to be unsubstituted or furthermore to be mono- or polysubstituted by the radical R 11 , and it being possible for the radical R 11 to represent one of the following groups: hydrogen, halogen, hydroxyl, formyl, carboxyl and their salts and esters, amino, nitro, C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl, aryl, and their esters and salts, and it being possible for the carbamoyl, sulfamoyl and amino groups of the radical R 11 to be unsubstituted or furthermore to be mono- or disubstituted by the radical R 12 , and it being possible for the radical R 1 2 to represent one of the following groups: hydrogen, hydroxyl, formyl, carboxyl and their salts and esters, amino, nitro, C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl or aryl.
Examples of the abovementioned compounds are:
1-hydroxy-1,2,3-triazole-4,5-dicarboxylic acid
1-phenyl-1H-1,2,3-triazole-3-oxide
5-chloro-1-phenyl -1H-1,2,3-triazole-3-oxide
5-methyl-1-phenyl-1H-1,2,3-triazole-3-oxide
4-(2,2-dimethylpropanoyl) -1-hydroxy-1H-1,2,3-triazole
4-hydroxy-2-phenyl-2H-1,2,3-triazole-1-oxide
2,4,5-triphenyl-2H-1,2,3-triazole-1-oxide
1-benzyl-1H-1,2,3-triazole-3-oxide
1-benzyl-4-chloro-1H-1,2,3-triazole-3-oxide
1-benzyl-4-bromo-1H-1,2,3-triazole-3-oxide
1-benzyl-4-methoxy-1H-1,2,3-triazole-3-oxide
Compounds of the general formula II are: ##STR5## where X is one of the following groups: (--N═N--), (--N═CR 4 --) p , (--CR 4 ═N--) p , (--CR 5 ═CR 6 ) p ##STR6## and p equals 1 or 2.
The radicals R 1 and R 4 to R 10 can be identical or different and independently of one another can represent one of the following groups: hydrogen, halogen, hydroxyl, formyl, carboxyl and the salts and esters thereof, amnino, nitro, C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl, aryl, sulfono, esters and salts thereof, sulfamoyl, carbamoyl, phospho, phosphono, phosphonooxy and their salts and esters, and it furthermore being possible for the amino, carbamoyl and sulfamoyl groups of the radicals R 1 and R 4 to R 10 to be unsubstituted or to be mono- or disubstituted by hydroxyl, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, and
it being possible for the C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl, aryl and aryl-C 1 -C 6 -alkyl groups of the radicals R 1 and R 4 to R 10 to be unsubstituted or furthermore to be mono- or polysubstituted by the radical R 12 , and it being possible for the radical R 12 to represent one of the following groups: hydrogen, halogen, hydroxyl, formyl, carboxyl and their salts and esters, amino, nitro, C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl, aryl, sulfono, sulfeno, sulfino and their esters and salts,
and it being possible for the carbamoyl, sulfamoyl and amino groups of the radical R 12 to be unsubstituted or furthermore to be mono- or disubstituted by the radical R 13 , and it being possible for the radical R 13 to represent one of the following groups: hydrogen, hydroxyl, formyl, carboxyl and their salts and esters, amino, nitro, C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl, aryl.
Examples of the abovementioned compounds are:
1-hydroxybenzimidazoles
1-hydroxybenzimidazole-2-carboxylic acid
1-hydroxybenzimidazole
2-methyl-1-hydroxybenzimidazole
2-phenyl-1-hydroxybenzimidazole
1-hydroxyindoles
2-phenyl-1-hydroxyindole
Substances of the general formula III are: ##STR7## where X is one of the following groups: (--N═N--), (--N═CR 4 --) m , (--CR 4 ═N--) m , (--CR 5 ═CR 6 --) m ##STR8## and m equals 1 or 2.
What has been said above for the radicals R 7 to R 10 and R 4 to R 6 also applies here.
R 14 can be: hydrogen, C 1 -C 10 -alkyl or C 1 -C 10 -alkyl-carbonyl whose C 1 -C 10 -alkyl and C 1 -C 10 -alkylcarbonyl can be unsubstituted or mono- or polysubstituted by a radical R 15 , it being possible for R 15 to represent one of the following groups: hydrogen, halogen, hydroxyl, formyl, carboxyl and salts and esters thereof, amino, nitro, C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl, sulfono, their esters and salts, sulfamoyl, carbamoyl, phospho, phosphono, phosphonooxy and their salts and esters, it being possible for the amino, carbamoyl and sulfamoyl groups of the radical R 15 furthermore to be unsubstituted or mono- or disubstituted by hydroxyl, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy.
Particularly preferred amongst the substances of the formula III are derivatives of 1-hydroxybenzotriazole and of the tautomeric benzotriazole 1-oxide, and their esters and salts (compounds of the formula IV) ##STR9##
The radicals R 7 to R 10 can be identical or different and independently of one another represent one of the following groups: hydrogen, halogen, hydroxyl, formyl, carboxyl and salts and esters thereof, amino, nitro, C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl, sulfono, esters and salts thereof, sulfamoyl, carbamoyl, phospho, phosphono, phosphonooxy and their salts and esters, it furthermore being possible for the amino, carbamoyl and sulfamoyl groups of the radicals R 7 to R 10 to be unsubstituted or to be mono- or disubstituted by hydroxyl, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy and it being possible for the C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl and aryl groups of the radicals R 7 to R 10 to be unsubstituted or furthermore mono- or polysubstituted by the radical R 16 , and it being possible for the radical R 16 to represent one of the following groups: hydrogen, halogen, hydroxyl, formyl, carboxyl and their salts and esters, amino, nitro, C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl, aryl, sulfono, sulfeno, sulfino and also their esters and salts, and it being possible for the carbamoyl, sulfamoyl and amino groups of the radical R 16 to be unsubstituted or furthermore mono- or disubstituted by the radical R 17 , and it being possible for the radical R 17 to represent one of the following groups: hydrogen, hydroxyl, formyl, carboxyl and their salts and esters, amino, nitro, C 1 -C 12 -alkyl, C 1 -C 6 -alkyloxy, carbonyl-C 1 -C 6 -alkyl, phenyl, aryl.
Examples of the abovementioned compounds are:
1-H-hydroxybenzotriazoles
1-hydroxybenzotriazole
1-hydroxybenzotriazole, sodium salt.
1-hydroxybenzotriazole, potassium salt
1-hydroxybenzotriazole, lithium salt
1-hydroxybenzotriazole, ammonium salt
1-hydroxybenzotriazole, calcium salt
1-hydroxybenzotriazole, magnesium salt
1-hydroxybenzotriazole-6-sulfonic acid
1-hydroxybenzotriazole-6-sulfonic acid, monosodium salt
1-hydroxybenzotriazole-6-carboxylic acid
1-hydroxybenzotriazole-6-N-phenylcarboxamide
5-ethoxy-6-nitro-1-hydroxybenzotriazole
4-ethyl-7-methyl-6-nitro-1-hydroxybenzotriazole
2,3-bis(4-ethoxyphenyl)-4,6-dinitro-2,3-dihydro-1-hydroxybenzotriazole
2,3-bis(2-bromo-4-methylphenyl)-4,6-dinitro-2,3-dihydro-1-hydroxybenzotriazole
2,3-bis(4-bromophenyl)-4,6-dinitro-2,3-dihydro-1-hydroxy-benzotriazole
2,3-bis(4-carboxyphenyl)-4,6-dinitro-2,3-dihydro-1-hydroxybenzotriazole
4,6-bis(trifluoromethyl)-1-hydroxybenzotriazole
5-bromo-1-hydroxybenzotriazole
6-bromo-1-hydroxybenzotriazole
4-bromo-7-methyl-1-hydroxybenzotriazole
5-bromo-7-methyl-6-nitro-1-hydroxybenzotriazole
4-bromo-6-nitro-1-hydroxybenzotriazole
6-bromo-4-nitro-1-hydroxybenzotriazole
4-chloro-1-hydroxybenzotriazole
5-chloro-1-hydroxybenzotriazole
6-chloro-1-hydroxybenzotriazole
6-chloro-5-isopropyl-1-hydroxybenzotriazole
5-chloro-6-methyl-1-hydroxybenzotriazole
6-chloro-5-methyl-1-hydroxybenzotriazole
4-chloro-7-methyl-6-nitro-1-hydroxybenzotriazole
4-chloro-5-methyl-1-hydroxybenzotriazole
5-chloro-4-methyl-1-hydroxybenzotriazole
4-chloro-6-nitro-1-hydroxybenzotriazole
6-chloro-4-nitro-1-hydroxybenzotriazole
7-chloro-1-hydroxybenzotriazole
6-diacetylamino-1-hydroxybenzotriazole
2,3-dibenzyl-4,6-dinitro-2,3-dihydro-1-hydroxybenzotriazole
4,6-dibromo-1-hydroxybenzotriazole
4,6-dichloro-1-hydroxybenzotriazole
5,6-dichloro-1-hydroxybenzotriazole
4,5-dichloro-1-hydroxybenzotriazole
4,7-dichloro-1-hydroxybenzotriazole
5,7-dichloro-6-nitro-1-hydroxybenzotriazole
5,6-dimethoxy-1-hydroxybenzotriazole
2,3-di-[2]naphthyl-4,6-dinitro-2,3-dihydro-1-hydroxybenzotriazole
4,6-dinitro-1-hydroxybenzotriazole
4,6-dinitro-2,3-diphenyl-2,3-dihydro-1-hydroxybenzotriazole
4,6-dinitro-2,3-di-p-tolyl-2,3-dihydro-1-hydroxybenzotriazole
5-hydrazino-7-methyl-4-nitro-1-hydroxybenzotriazole
5,6-dimethyl-1-hydroxybenzotriazole
4-methyl-1-hydroxybenzotriazole
5-methyl-1-hydroxybenzotriazole
6-methyl-1-hydroxybenzotriazole
5-(1-methylethyl)-1-hydroxybenzotriazole
4-methyl-6-nitro-1-hydroxybenzotriazole
6-methyl-4-nitro-1-hydroxybenzotriazole
5-methoxy-1-hydroxybenzotriazole
6-methoxy-1-hydroxybenzotriazole
7-methyl-6-nitro-1-hydroxybenzotriazole
4-nitro-1-hydroxybenzotriazole
6-nitro-1-hydroxybenzotriazole
6-nitro-4-phenyl-1-hydroxybenzotriazole
5-phenylmnethyl-1-hydroxybenzotriazole
4-trifluoromethyl1-hydroxybenzotriaz ole
5-trifluoromethyl-1-hydroxybenzotriazole
6-trifluoromethyl-1-hydroxybenzotriazole
4,5,6,7-tetrachloro-1-hydroxybenzotriazole
4, 5,6,7-tetrafluoro-1-hydroxybenzotriazole
6-tetrafluoroethyl-1-hydroxybenzotriazole
4,5,6-trichloro-1-hydroxybenzotriazole
4, 6,7-trichloro-1-hydroxybenzotriazole
6-sulfamido-1-hydroxybenzotriazole
6-N,N-diethylsulfamido-1-hydroxybenzotriazole
6-N-methylsulfamido-1-hydroxybenzotriazole
6-(1H-1,2,4-triazol-1-ylmethyl)-1-hydroxybenzotriazole
6-(5,6,7,8-tetrahydroimnidazo[1,5-a]pyridin-5-yl)-1-hydroxybenzotriazole
6-(phenyl-1H-1,2,4-triazol-1-ylmethyl)-1-hydroxybenzotriazole
6-[(5-methyl-1H-imidazo-1-yl) phenylmnethyl]-1-hydroxybenzotriazole
6-[(4-methyl-1H-imidazo-1-yl)phenylmethyl]-1-hydroxybenzotriazole
6-[(2-methyl-1H-imidazo-1-yl)phenylmethyl]-1-hydroxybenzotriazole
6-(1H-imidazol-1-ylphenylmethyl)-1-hydroxybenzotriazole
5-(1H-imidazol-1-ylphenylmethyl)-1-hydroxybenzotriazole
6-[1-(1H-imidazol-1-yl)ethyl]-1-hydroxybenzotriazole monohydrochloride
3H-benzotriazole 1-oxides
3H-benzotriazole 1-oxide
6-acetyl-3H-benzotriazole 1-oxide
5-ethoxy-6-nitro-3H-benzotriazole 1-oxide
4-ethyl-7-methyl-6-nitro-3H-benzotriazole 1-oxide
6-amino-3,5-dimethyl-3H-benzotriazole 1-oxide
6-amino-3-methyl-3H-benzotriazole 1-oxide
5-bromo-3H-benzotriazole 1-oxide
6-bromo-3H-benzotriazole 1-oxide
4-bromo-7-methyl-3H-benzotriazole 1-oxide
5-bromo-4-chloro-6-nitro-3H-benzotriazole 1-oxide
4-bromo-6-nitro-3H-benzotriazole 1-oxide
6-bromo-4-nitro-3H-benzotriazole 1-oxide
5-chloro-3H-benzotriazole 1-oxide
6-chloro-3H-benzotriazole 1-oxide
4-chloro-6-nitro-3H-benzotriazole 1-oxide
4 6-dibromo-3H-benzotriazole 1-oxide
4,6-dibromo-3-methyl-3H-benzotriazole 1-oxide
4,6-dichloro-3H-benzotriazole 1-oxide
4,7-dichloro-3H-benzotriazole 1-oxide
5,6-dichloro-3H-benzotriazole 1-oxide
4,6-dichloro-3-methyl-3H-benzotriazole 1-oxide
5,7-dichloro-6-nitro-3H-benzotriazole 1-oxide
3,6-dimethyl-6-nitro-3H-benzotriazole 1-oxide
3,5-dimethyl-6-nitro-3H-benzotriazole 1-oxide
3-methyl-3H-benzotriazole 1-oxide
5-methyl-3H-benzotriazole 1-oxide
6-methyl-3H-benzotriazole 1-oxide
6-methyl-4-nitro-3H-benzotriazole 1-oxide
7-methyl-6-nitro-3H-benzotriazole 1-oxide
5-chloro-6-nitro-3H-benzotriazole 1-oxide
2H-benzotriazole 1-oxides
2-(4-acetoxyphenyl)-2H-benzotriazole 1-oxide
6-acetylamino-2-phenyl-2H-benzotriazole 1-oxide
2-(4-ethylphenyl)-4,6-dinitro-2H-benzotriazole 1-oxide
2-(3-aminophenyl)-2H-benzotriazole 1-oxide
2-(4-aminophenyl)-2H-benzotriazole 1-oxide
6-amino-2-phenyl-2H-benzotriazole 1-oxide
5-bromo-4-chloro-6-nitro-2-phenyl-2H-benzotriazole 1-oxide
2-(4-bromophenyl)-2H-benzotriazole 1-oxide
5-bromo-2-phenyl-2H-benzotriazole 1-oxide
6-bromo-2-phenyl-2H-benzotriazole 1-oxide
2-(4-bromophenyl)-4,6-dinitro-2H-benzotriazole 1-oxide
2-(4-bromophenyl)-6-nitro-2H-benzotriazole 1-oxide
5-chloro-2-(2-chlorophenyl)-2H-benzotriazole 1-oxide
5-chloro-2-(3-chlorophenyl)-2H-benzotriazole 1-oxide
5-chloro-2-(2-chlorophenyl)-2H-benzotriazole 1-oxide
5-chloro-2-(3-chlorophenyl)-2H-benzotriazole 1-oxide
5-chloro-2-(2,4-dibromophenyl)-2H-benzotriazole 1-oxide
5-chloro-2-(2,5-dimethylphenyl)-2H-benzotriazole 1-oxide
5-chloro-2-(4-nitrophenyl)-2H-benzotriazole 1-oxide
5-chloro-6-nitro-2-phenyl-2H-benzotriazole 1-oxide
2-[4-(4-chloro-3-nitrophenylazo)-3-nitrophenyl]-4,6-dinitro-2H-benzotriazole 1-oxide
2-(3-chloro-4-nitrophenyl)-4,6-dinitro-2H-benzotriazole 1-oxide
2-(4-chloro-3-nitrophenyl)-4,6-dinitro-2H-benzotriazole 1-oxide
4-chloro-6-nitro-2-p-tolyl-2H-benzotriazole 1-oxide
5-chloro-6-nitro-2-p-tolyl-2H-benzotriazole 1-oxide
6-chloro-4-nitro-2-p-tolyl-2H-benzotriazole 1-oxide
2-(2-chlorophenyl)-2H-benzotriazole 1-oxide
2-(3-chlorophenyl)-2H-benzotriazole 1-oxide
2-(4-chlorophenyl)-2H-benzotriazole 1-oxide
5-chloro-2-phenyl-2H-benzotriazole 1-oxide
2-[4-(4-chlorophenylazo)-3-nitrophenyl]-4,6-dinitro-2H-benzotriazole 1-oxide
2-(2-chlorophenyl)-4,6-dinitro-2H-benzotriazole 1-oxide
2-(3-chlorophenyl)-4,6-dinitro-2H-benzotriazole 1-oxide
2-(4-chlorophenyl)-4,6-dinitro-2H-benzotriazole 1-oxide
2-{4-[N'-(3-chlorophenyl)hydrazino]-3-nitrophenyl}-4,6-dinitro-2H-benzotriazole 1-oxide
2-{4-[N'-(4-chlorophenyl)hydrazino]-3-nitrophenyl}-4,6-dinitro-2H-benzotriazole 1-oxide
2-(2-chlorophenyl)-6-methyl-2H-benzotriazole 1-oxide
2-(3-chlorophenyl)-6-methyl-2H-benzotriazole 1-oxide
2-(4-chlorophenyl)-6-methyl-2H-benzotriazole 1-oxide
2-(3-chlorophenyl)-6-nitro-2H-benzotriazole 1-oxide
2-(4-chlorophenyl)-6-nitro-2H-benzotriazole 1-oxide
2-(4-chlorophenyl)-6-picrylazo-2H-benzotriazole 1-oxide
5-chloro-2-(2,4,5-trimethylphenyl)-2H-benzotriazole 1-oxide
4,5-dibromo-6-nitro-2-p-tolyl-2H-benzotriazole 1-oxide
4,5-dichloro-6-nitro-2-phenyl-2H-benzotriazole 1-oxide
4,5-dichloro-6-nitro-2-p-tolyl-2H-benzotriazole 1-oxide
4,7-dichloro-6-nitro-2-p-tolyl-2H-benzotriazole 1-oxide
4,7-dimethyl-6-nitro-2-phenyl-2H-benzotriazole 1-oxide
2-(2,4-dimethylphenyl)-4,6-dinitro-benzotriazole 1-oxide
2-(2,5-dimethylphenyl)-4,6-dinitro-2H-benzotriazole 1-oxide
2-(2,4-dimethylphenyl)-6-nitro-2H-benzotriazole 1-oxide
2-(2,5-dimethylphenyl)-6-nitro-2H-benzotriazole 1-oxide
4,6-dinitro-2-[3-nitro-4-(N'-phenylhydrazino)phenyl]-2H-benzotriazole 1-oxide
4,6-dinitro-2-[4-nitro-4-(N'-phenylhydrazino)phenyl]-2H-benzotriazole 1-oxide
4,6-dinitro-2-phenyl-2H-benzotriazole 1-oxide
2-(2,4-dinitrophenyl)-4,6-dinitro-2H-benzotriazole 1-oxide
2-(2,4-dinitrophenyl)-6-nitro-2H-benzotriazole 1-oxide
4,6-dinitro-2-o-tolyl-2H-benzotriazole 1-oxide
4,6-dinitro-2-p-tolyl-2H-benzotriazole 1-oxide
4,6-dinitro-2-(2,4,5-trimethylphenyl)-2H-benzotriazole 1-oxide
2-(4-methoxyphenyl)-2H-benzotriazole 1-oxide
2-(4-methoxyphenyl)-6-methyl-2H-benzotriazole 1-oxide
5-methyl-6-nitro-2-m-tolyl-2H-benzotriazole 1-oxide
5-methyl-6-nitro-2-o-tolyl-2H-benzotriazole 1-oxide
5-methyl-6-nitro-2-p-tolyl-2H-benzotriazole 1-oxide
6-methyl-4-nitro-2-p-tolyl-2H-benzotriazole 1-oxide
6-methyl-2-phenyl-2H-benzotriazole 1-oxide
4-methyl-2-m-tolyl-2H-benzotriazole 1-oxide
4-methyl-2-o-tolyl-2H-benzotriazole 1-oxide
4-methyl-2-p-tolyl-2H-benzotriazole 1-oxide
6-methyl-2-m-tolyl-2H-benzotriazole 1-oxide
6-methyl-2-o-tolyl-2H-benzotriazole 1-oxide
6-methyl-2-p-tolyl-2H-benzotriazole 1-oxide
2-[1]naphthyl-4,6-dinitro-2H-benzotriazole 1-oxide
2-[2]naphthyl-4,6-dinitro-2H-benzotriazole 1-oxide
2-[1]naphthyl-6-nitro-2H-benzotriazole 1-oxide
2-[2]naphthyl-6-nitro-2H-benzotriazole 1-oxide
2-(3-nitrophenyl)-2H-benzotriazole 1-oxide
6-nitro-2-phenyl-2H-benzotriazole 1-oxide
4-nitro-2-p-tolyl-2H-benzotriazole 1-oxide
6-nitro-2-o-tolyl-2H-benzotriazole 1-oxide
6-nitro-2-p-tolyl-2H-benzotriazole 1-oxide
6-nitro-2-(2,4,5-trimethylphenyl)-2H-benzotriazole 1-oxide
2-phenyl-2H-benzotriazole 1-oxide
2-o-tolyl-2H-benzotriazole 1-oxide
2-p-tolyl-2H-benzotriazole 1-oxide
The mediator can preferably furthermore be selected amongst the group consisting of cyclic N-hydroxy compounds having at least one optionally substituted five or six-membered ring which contains the structure mentioned in formula V ##STR10## and their salts, ethers or esters, where B and D are identical or different and are O, S or NR 18 ,
R 18 being hydrogen, hydroxyl, formyl, carbamoyl, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, amino, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, carbonyl-C 1 -C 6 -alkyl, phospho, phosphono, phosphonooxy radical, ester or salt of the phosphonooxy radical,
it being possible for carbamoyl, sulfamoyl, amino and phenyl radicals to be unsubstituted or mono- or polysubstituted by a radical R 19 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl and carbonyl C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 19 ,
R 19 being identical or different and being a hydroxyl, formyl or carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono or ester or salt of the sulfono radical, sulfamoyl, nitro, amino, phenyl, C 1 -C 5 -alkyl or C 1 -C 5 -alkoxy radical.
The mediator is preferably selected from the group of the compounds of the general formula VI, VII, VIII or IX, ##STR11## where B and D have the meanings which have already been mentioned and the radicals R 20 -R 35 are identical or different and are a halogen radical, carboxyl radical, salt or ester of a carboxyl radical or have the meanings mentioned for R 18 , where R 26 and R 27 , or R 28 and R 29 , respectively, must not simultaneously be a hydroxyl or amino radical, and where, if appropriate, in each case two of the substituents R 20 -R 23 , R 24 -R 25 , R 26 -R 29 , R 30 -R 35 can be linked to give a ring --E--, --E-- having one of the following meanings:
(--CH═CH)-- n , where n=1 to 3, --CH═CH--CH═N-- or ##STR12## and where, if appropriate, the radicals R 26 -R 29 can also be linked to each other by one or more bridging elements --F--, --F-- being identical or different and having one of the following meanings: --O--, --S, --CH 2 --, --CR 36 ═CR 37 ; R 36 and R 37 being identical or different and having the meaning of R 20 .
Especially preferred as mediators are compounds of the general formulae VI, VII, VIII or IX, where B and D are O or S.
Examples of such compounds are N-hydroxyphthalimide and optionally substituted N-hydroxyphthalimide derivatives, N-hydroxymaleimide and optionally substituted N-hydroxymaleimide derivatives, N-hydroxynaphthalimide and optionally substituted N-hydroxynaphthalimide derivatives, N-hydroxysuccinimide and optionally substituted N-hydroxysuccinimide derivatives, preferably those where the radicals R 26 -R 29 are linked in the form of polycycles.
Particularly preferred as mediator are N-hydroxyphthalimide, 4-amino-N-hydroxyphthalimide and 3-amino-N-hydroxyphthalimide.
Examples of compounds of the formula VI which are suitable as mediator are:
N-hydroxyphthalimide,
4-amino-N-hydroxyphthalimide,
3-amino-N-hydroxyphthalimide,
N-hydroxybenzene-1,2,4-tricarboximide,
N,N'-dihydroxypyromellitic diimide,
N,N'-dihydroxybenzophenone-3,3',4,4'-tetracarboxylic duimide.
Examples of compounds of the formula VII which are suitable as mediator are:
N-hydroxymaleimide,
N-hydroxy-pyridine-2,3-dicarboximide.
Examples of compounds of the formula VIII which are suitable as mediator are:
N-hydroxysuccinimide,
N-hydroxytartarimide,
N-hydroxy-5-norbornene-2,3-dicarboximide,
exo--N-hydroxy-7-oxabicyclo[2.2.1]-hept-5-ene-2,3-dicarboximide,
N-hydroxy-cis-cyclohexane-1,2-dicarboximide,
N-hydroxy-cis-4-cyclohexene-1,2-dicarboximide.
An example of the compound of the formula IX which is suitable as mediator is:
N-hydroxynaphthalimide-sodium salt.
An example of a compound with a six-membered ring containing the structure mentioned in formula V and suitable as mediator is:
N-hydroxyglutarimide.
The compounds which have been mentioned by way of example are also suitable as mediator in the form of their salts or esters.
Also suitable as mediator are compounds selected from the group of the N-aryl-N-hydroxy-amides.
Amongst these, compounds which are preferably employed as mediators are those of the general formula X, ##STR13## and their salts, ethers or esters, where G is a monovalent homo- or heteroaromatic mono- or binuclear radical and
L is a divalent homo- or heteroaromatic mono- or binuclear radical, and
it being possible for these aromatics to be substituted by one or more identical or different radicals R 38 selected from the group consisting of halogen, hydroxyl, formyl, cyano, carbamoyl, carboxyl radical, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, nitroso, amino, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, carbonyl-C 1 -C 6 -alkyl, phospho, phosphono or phosphonooxy radical, ester or salt of the phosphonooxy radical, and it being possible for carbamoyl, sulfamoyl, amino and phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 39 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, carbonyl-C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 39 ,
R 39 being identical or different and being hydroxyl, formyl, cyano, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, nitroso, amino, phenyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy or C 1 -C 5 -alkylcarbonyl radical and
it being possible for in each case two radicals R 38 or R 39 to be linked, in pairs, via a bridge [--CR 40 R 41 --] m where m equals 0, 1, 2, 3 or 4 and
R 40 and R 41 are identical or different and are a carboxyl radical, ester or salt of the carboxyl radical, phenyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy or C 1 -C 5 -alkylcarbonyl radical and it being possible for one or more nonadjacent groups [--CR 40 R 41 --] to be replaced by oxygen, sulfur or by an imino radical which is optionally substituted by C 1 to C 5 -alkyl radical and it being possible for two adjacent groups [--CR 40 R 41 --] to be replaced by a group [--CR 40 ═CR 41 --] and I is a monovalent acid radical, present in amide form, of acids selected from the group consisting of carboxylic acid having up to 20 C atoms, carbonic acid, monoester of carbonic acid or of carbamic acid, sulfonic acid, phosphonic acid, phosphoric acid, monoester of phosphoric acid, diester of phosphoric acid and
K is a divalent acid radical, present in amide form, of acids selected from the group consisting of mono- and dicarboxylic acids having up to 20 C atoms, carbonic acid, sulfonic acid, phosphonic acid, phosphoric acid or monoester of phosphoric acid.
Especially preferred as mediators are compounds of the general formula XIII, XIV, XV, XVI or XVII: ##STR14## and their salts, ethers or esters, where Ar 1 is a monovalent homo- or heteroaromatic mononuclear aryl radical and
Ar 2 is a divalent homo- or heteroaromatic mononuclear aryl radical,
each of which can be substituted by one or more identical or different radicals R 44 selected from the group consisting of hydroxyl, cyano, carboxyl radical, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, nitro, nitroso, amino, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl or carbonyl-C 1 -C 6 -alkyl radical,
it being possible for amino radicals to be unsubstituted or mono- or polysubstituted by a radical R 45 and it being possible for the C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl and carbonyl-C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 45 ,
R 45 being identical or different and being hydroxyl, carboxyl radical, ester or salt of the carboxyl radical, sulfono, nitro, amino, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy or C 1 -C 5 -alkylcarbonyl radical and
it being possible for in each case two radicals R 44 to be linked, in pairs, via a bridge [--CR 40 R 41 --] m where m equals 0, 1, 2, 3 or 4 and
R 40 and R 41 have the meanings which have already been mentioned and one or more nonadjacent groups [--CR 40 R 41 --] can be replaced by oxygen, sulfur or by an imino radical which is optionally substituted by a C 1 to C 5 -alkyl radical, and two adjacent groups [--CR 40 R 41 --] can be replaced by a group [--CR 40 ═CR 41 --],
R 42 is identical or different monovalent radicals selected from the group consisting of hydrogen, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy or C 1 -C 10 -carbonyl radical, it being possible for phenyl radicals to be unsubstituted or mono- or polysubstituted by a radical R 46 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy and C 1 -C 10 -carbonyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 46 ,
R 46 being identical or different and being hydroxyl, formyl, cyano, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, nitroso, amino, phenyl, C 1 -C 5 -alkyl or C 1 -C 5 -alkoxy radical and
R 43 being divalent radicals selected from the group consisting of ortho-, meta-, para-phenylene, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkylene or C 1 -C 5 -alkylenedioxy radical, it being possible for the phenylene radicals to be unsubstituted or mono- or polysubstituted by a radical R 46 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl or C 1 -C 5 -alkoxy radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 46 ,
p being 0 or 1 and
q being an integer from 1 to 3.
Preferably, Ar 1 is a phenyl radical and Ar 2 an ortho-phenylene radical, it being possible for Ar 1 to be substituted by up to five and for Ar 2 to be substituted by up to four identical or different radicals selected from the group consisting of C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, carboxyl radical, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, hydroxyl, cyano, nitro, nitroso and amino radical, it being possible for amino radicals to be substituted by two different radicals selected from the group consisting of hydroxyl and C 1 -C 3 -alkylcarbonyl.
Preferably, R 42 is a monovalent radical selected from the group consisting of hydrogen, phenyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy radical, it being possible for the C 1 -C 12 -alkyl radicals and the C 1 -C 5 -alkoxy radicals to be saturated or unsaturated, branched or unbranched.
Preferably, R 43 is divalent radicals selected from the group consisting of ortho- or para-phenylene, C 1 -C 12 -alkylene, C 1 -C 5 -alkylenedioxy radical, it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl and C 1 -C 5 -alkoxy radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical
R 46 is preferably carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, phenyl or C 1 -C 3 -alkoxy radical.
Examples of compounds which can be employed as mediators are N-hydroxyacetanilide, N-hydroxypivaloylanilide, N-hydroxyacrylanilide, N-hydroxybenzoylanilide, N-hydroxymethylsulfonylanilide, N-hydroxy-N-phenylmethylcarbamate, N-hydroxy-3-oxo-butyrylanilide, N-hydroxy-4-cyanoacetanilide, N-hydroxy-4-methoxyacetanilide, N-hydroxyphenacetin, N-hydroxy-2,3-dimethylacetanilide, N-hydroxy-2-methylacetanilide, N-hydroxy-4-methyl-acetanilide, 1-hydroxy-3,4-dihydroquinolin-(1H)-2-one, N,N'-dihydroxy-N,N'-diacetyl-1,3-phenylenediamine, N,N'-dihydroxysuccinanilide, N,N'-dihydroxymaleianilide, N,N'-dihydroxyoxalanilide, N,N'-dihydroxyphosphoranilide, N-acetoxyacetanilide, N-hydroxymethyloxalylanilide, N-hydroxymaleianilide.
Mediators which are preferably used are N-hydroxyacetanilide, N-hydroxyformanilide, N-hydroxy-N-phenylmethylcarbamate, N-hydroxy-2-methylacetanilide, N-hydroxy-4-methylacetanilide, 1-hydroxy-3,4-dihydroquinolin-(1H)-2-one and N-acetoxyacetanilide.
The mediator can furthermore be selected from the group of the N-alkyl-N-hydroxy-amides.
Mediators which are preferably employed are compounds of the general formula (XVIII) or (XIX) ##STR15## and their salts, ethers or esters, where M is identical or different and is a monovalent linear or branched or cyclic or polycyclic saturated or unsaturated alkyl radical having 1-24 C atoms, and
it being possible for this alkyl radical to be substituted by one or more radicals R 48 , which are identical or different and are selected from the group consisting of hydroxyl, mercapto, formyl, carbamoyl, carboxyl, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, nitroso, amino, hydroxylamino, phenyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, phospho, phosphono, phosphonooxy radical, ester or salt of the phosphonooxy radical, and
it being possible for carbamoyl, sulfamoyl, amino, hydroxylamino, mercapto and phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 48 , and it being possible for the C 1 -C 5 -alkoxy and C 1 -C 10 -carbonyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 48 ,
R 48 being identical or different and being hydroxyl, formyl, cyano, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, nitroso, amino, phenyl, benzoyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy or C 1 -C 5 -alkylcarbonyl radical, and it being possible for methylene groups which are not in the α-position to be replaced by oxygen, sulfur or by an optionally mono-substituted imino radical, and where
N is a monovalent acid radical, present in amide form, of acids selected from the group consisting of aliphatic or mono- or binuclear aromatic or mono- or binuclear hetero-aromatic carboxylic acids having up to 20 C atoms, carbonic acid, monoester of carbonic acid or of carbamic acid, sulfonic acid, phosphonic acid, phosphoric acid, monoester of phosphoric acid, diester of phosphoric acid, and
T is a divalent acid radical, present in amide form, of acids selected from the group consisting of aliphatic, mono- or binuclear aromatic or mono- or binuclear hetero-aromatic dicarboxylic acids having up to 20 C atoms, carbonic acid, sulfonic acid, phosphonic acid, phosphoric acid, monoester of phosphoric acid, and
it being possible for alkyl radicals of the aliphatic acids N and T, present in amide form, to be linear or branched and/or to be saturated or unsaturated in the cycle and/or polycycle and to contain 0-24 carbon atoms and to be unsubstituted or to be mono- or polysubstituted by the radical R 47 and
it being possible for aryl and heteroaryl radicals of the aromatic or heteroaromatic acids N and T. present in amide form, to be substituted by one or more radicals R 49 which are identical or different and are selected from the group consisting of hydroxyl, mercapto, formyl, cyano, carbamoyl, carboxyl, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, nitroso, amino, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, phospho, phosphono, phosphonooxy radical, ester or salt of the phosphonooxy radical and
it being possible for carbamoyl, sulfamoyl, amino, mercapto and phenyl radicals to be unsubstituted or mono- or polysubstituted by the radical R 48 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl-C l-C 5 -alkoxy and C 1 -C 10 -carbonyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by the radical R 48 .
Especially preferred as mediators are compounds of the general formula (XX, XXI, XXII or XXIII): ##STR16## and their salts, ethers or esters, where Alk 1 is identical or different and is a monovalent linear or branched or cyclic or polycyclic saturated or unsaturated alkyl radical having 1-10 C atoms,
it being possible for this alkyl radical to be substituted by one or more radicals R 50 which are identical or different and are selected from the group consisting of hydroxyl, formyl, carbamoyl, carboxyl, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, nitroso, amino, hydroxylamino, phenyl, C 1 -C 5 -alkoxy or C 1 -C 5 -carbonyl radicals and it being possible for carbamoyl, sulfamoyl, amino, hydroxylamino and phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 51 and it being possible for the C 1 -C 5 -alkoxy and C 1 -C 10 -carbonyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 51 ,
R 51 being identical or different and being hydroxyl, formyl, cyano, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, amino, phenyl, benzoyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy or C 1 -C 5 -alkylcarbonyl radical and
it being possible for methylene groups which are not in the α-position to be replaced by oxygen, sulfur or by an optionally monosubstituted imino radical and R 52 being identical or different monovalent radicals selected from the group consisting of hydrogen, phenyl, pyridyl, furyl, pyrrolyl, thienyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 10 -alkoxy or C 1 -C 10 -carbonyl radical,
it being possible for phenyl, pyridyl, furyl, pyrrolyl and thienyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 7 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy and C 1 -C 10 -carbonyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 53 and
R 53 is identical or different and is hydroxyl, formyl, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, amino, phenyl, C 1 -C 5 -alkyl or C 1 -C 5 -alkoxy radical and
R 54 is divalent radicals selected from the group consisting of phenylene, pyridylene, thienylene, furylene, pyrrolylene, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkylene or C 1 -C 5 -alkylenedioxy radical, it being possible for phenylene, pyridylene, thienylene, furylene and pyrrolylene to be unsubstituted or to be mono- or polysubstituted by a radical R 53 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl and C 1 -C 5 -alkoxy radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 53 , p being 0 or 1.
Very especially preferred as mediators are compounds of the general formulae (XX-XXIII), where Alk 1 is identical or different and is a monovalent linear or branched or cyclic saturated or unsaturated alkyl radical having 1-10 C atoms,
it being possible for this alkyl radical to be substituted by one or more radicals R 50 which are identical or different and are selected from the group consisting of hydroxyl, carbamoyl, carboxyl, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, amino, phenyl, C 1 -C 5 -alkoxy or C 1 -C 5 -carbonyl radicals and
it being possible for carbamoyl, sulfamoyl, amino and phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 51 and it being possible for the C 1 -C 5 -alkoxy and C 1 -C 10 -carbonyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 51 ,
R 51 being identical or different and being hydroxyl, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, amino, phenyl, benzoyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy or C 1 -C 5 -alkylcarbonyl radical and
R 52 being identical or different monovalent radicals selected from the group consisting of hydrogen, phenyl, furyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 10 -alkoxy or C 1 -C 10 -carbonyl radical,
it being possible for phenyl and furyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 53 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy and C 1 -C 10 -carbonyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 53 ,
R 53 being identical or different and being a carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, phenyl, C 1 -C 5 -alkyl or C 1 -C 5 -alkoxy radical and R 54 is a divalent radical selected from the group consisting of phenylene, furylene, C 1 -C 12 -alkylene and C 1 -C 5 -alkylenedioxy radical, it being possible for phenylene and furanylene to be unsubstituted or to be mono- or polysubstituted by a radical R 53 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl and C 1 -C 5 -alkoxy radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 53 ,
p being 0 or 1.
Examples of compounds which can be employed as mediators are
N-hydroxy-N-methylbenzamide, N-hydroxy-N-methylbenzene-sulfonamide, N-hydroxy-N-methyl-p-toluenesulfonamide, N-hydroxy-N-methylfuran-2-carboxamide, N-hydroxy-N-methyl-thiophene-2-carboxamide, N,N'-dihydroxy-N,N'-dimethyl-phthalamide, N,N'-dihydroxy-N,N'-dimethylisophthalamide, N,N'-dihydroxy-N,N'-dimethylterephthalamide, N,N'-dihydroxy-N,N'-dimethylbenzene-1,3-disulfonamide, N,N'-dihydroxy-N,N'-dimethylfuran-3,4-dicarboxamide, N-hydroxy-N-tert-butylbenzamide, N-hydroxy-N-tert-butyl-benzenesulfonamide, N-hydroxy-N-tert-butyl-p-toluene-sulfonamide,
N-hydroxy-N-tert-butylfuran-2-carboxamide,
N-hydroxy-N-tert-butylthiophene-2-carboxamide,
N,N'-dihydroxy-N,N'-di-tert-butylphthalamide,
N,N'-dihydroxy-N,N'-di-tert-butylisophthalamide,
N,N'-dihydroxy-N,N'-di-tert-butylterephthalamide,
N,N'-dihydroxy-N,N'-di-tert-butylbenzene-1,3-disulfonamide,
N,N'-dihydroxy-N,N'-di-tert-butylfuran-3,4-dicarboxamide,
N-hydroxy-N-cyclohexylbenzamide, N-hydroxy-N-cyclohexylbenzenesulfonamide,
N-hydroxy-N-cyclohexyl-p-toluenesulfonamide,
N-hydroxy-N-cyclohexylfuran-2-carboxamide,
N-hydroxy-N-cyclohexylthiophene-2-carboxamide,
N,N'-dihydroxy-N,N'-dicyclohexylphthalamide,
N,N'-dihydroxy-N,N'-dicyclohexylisophthalamide,
N,N'-dihydroxy-N,N'-dicyclohexylterephthalamide,
N,N'-dihydroxy-N,N'-dicyclohexylbenzene-1,3-disulfonamide,
N,N'-dihydroxy-N,N'-dicyclohexylfuran-3,4-dicarboxamide,
N-hydroxy-N-isopropylbenzamide, N-hydroxy-N-isopropylbenzenesulfonamide, N-hydroxy-N-isopropyl-p-toluenesulfonamide, N-hydroxy-N-isopropylfuran-2-carboxamide, N-hydroxy-N-isopropylthiophene-2-carboxamide, N,N'-dihydroxy-N,N -diisopropylphthalamide, N,N'-dihydroxy-N,N'-diisopropylisophthala mide, N,N'-dihydroxy-N,N'-diisopropylterephthalainide, N,N'-dihydroxy-N,N'-diisopropylbenzene-1,3-disulfonamide, N,N'-dihydroxy-N,N'-diisopropylfuran-3,4-dicarboxamide, N-hydroxy-N-methylacetamide, N-hydroxy-N-tert-butylacetamide, N-hydroxy-N-isopropylacetamide, N-hydroxy-N-cyclohexylacetamide, N-hydroxy-N-methylpivalamide, N-hydroxy-N-isopropyl-pivalamide, N-hydroxy-N-methylacrylamide, N-hydroxy-N-tert-butylacrylamide, N-hydroxy-N-isopropylacrylamide, N-hydroxy-N-cyclohexylacrylamide, N-hydroxy-N-methylmethanesulfonamide, N-hydroxy-N-isopropylmethanesulfonamide, N-hydroxy-N-isopropylmethylcarbamate, N-hydroxy-N-methyl-3-oxobutyramide, N,N'-dihydroxy-N,N'-dibenzoylethylenediamine, N,N'-dihydroxy-N,N'-dimethylsuccinamide,
N,N'-dihydroxy-N,N'-di-tert-butylmaleamide,
N-hydroxy-N-tert-butylmaleamide,
N,N'-dihydroxy-N,N'-di-tert-butyloxalamide,
N,N'-dihydroxy-N,N'-di-tert-butylphosphoramide.
Compounds which are preferably selected as mediators are from the group consisting of N-hydroxy-N-methylbenzamide, N-hydroxy-N-methylbenzenesulfonamide, N-hydroxy-N-methyl-p-toluenesulfonamide, N-hydroxy-N-methylfuran-2-carboxamide, N,N'-dihydroxy-N,N'-dimethylphthalamide, N,N'-dihydroxy-N,N'-dimethylterephthalamide,
N,N'-dihydroxy-N,N'-dimethylbenzene-1,3-disulfonamide,
N-hydroxy-N-tert-butylbenzamide,
N-hydroxy-N-tert-butylbenzenesulfonamide,
N-hydroxy-N-tert-butyl-p-toluenesulfonamide,
N-hydroxy-N-tert-butylfuran-2-carboxamide,
N,N'-dihydroxy-N,N'-di-tert-butylterephthalamide, N-hydroxy-N-isopropylbenzamide, N-hydroxy-N-isopropyl-p-toluenesulfonamide, N-hydroxy-N-isopropylfuran-2-carboxamide, N,N'-dihydroxy-N,N'-diisopropylterephthalamide, N,N'-dihydroxy-N,N'-diisopropylbenzene-1,3-disulfonamide, N-hydroxy-N-methyl-acetamide, N-hydroxy-N-tert-butylacetamide, N-hydroxy-N-isopropylacetamide, N-hydroxy-N-cyclohexylacetamide, N-hydroxy-N-methylpivalamide, N-hydroxy-N-tert-butyl-acrylamide, N-hydroxy-N-isopropylacrylamide, N-hydroxy-N-methyl-3-oxobutyramide, N,N'-dihydroxy-N,N'-dibenzoylethylenediamine,
N,N'-dihydroxy-N,N'-di-tert-butylmaleamide,
N-hydroxy-N-tert-butylmaleamide,
N,N'-dihydroxy-N,N'-di-tert-butyloxalamide.
The mediator can furthermore be selected from the group of the oximes of the general formula XXIV or XXV ##STR17## and their salts, ethers or esters, where U is identical or different and is O, S or NR 55 ,
R 55 being hydrogen, hydroxyl, formyl, carbamoyl, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, amino, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, carbonyl-C 1 -C 6 -alkyl, phospho, phosphono or phosphonooxy radical, ester or salt of the phosphonooxy radical,
it being possible for carbamoyl, sulfamoyl, amino and phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 56 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl and carbonyl-C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 56 ,
R 56 being identical or different and being hydroxyl, formyl, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, ester or salt of the sulfono radical, sulfamoyl, nitro, amino, phenyl, C 1 -C 5 -alkyl or C 1 -C 5 -alkoxy radical and
the radicals R 57 and R 58 being identical or different and being halogen, carboxyl radical, ester or salt of the carboxyl radical, or having the meanings mentioned for R 55 , or being linked to a ring [--CR 61 R 62 ] n where n equals 2, 3 or 4 and
R 59 and R 60 having the meanings mentioned for R 55 and R 61 and R 62 being identical or different and being halogen, carboxyl radical, ester or salt of the carboxyl radical, or having the meanings mentioned for R 55 .
Especially preferred as mediators are compounds of the general formula XXIV where U is O or S and the remaining radicals have the meanings mentioned above. An example of such a compound is dimethyl 2-hydroxyiminomalonate.
Furthermore especially preferred as mediators are isonitroso derivatives of cyclic ureides of the general formula XXV. Examples of such compounds are 1-methylvioluric acid, 1,3-dimethylvioluric acid, thiovioluric acid, alloxane 4,5-dioxime.
Particularly preferred as mediator is alloxane 5-oxime hydrate (violuric acid) and/or its esters, ethers or salts.
The mediator can furthermore be selected from the group of the vicinally nitroso-substituted aromatic alcohols of the general formula XXVI or XXVII ##STR18## and their salts, ethers or esters, where R 63 , R 64 , R 65 and R 66 are identical or different and are hydrogen, halogen, hydroxyl, formyl, carbamoyl, carboxyl radical, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, nitroso, cyano, amino, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, carbonyl-C 1 -C 6 -alkyl, phospho, phosphono or phosphonooxy radical, ester or salt of the phosphonooxy radical,
it being possible for carbamoyl, sulfamoyl, amino and phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 67 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl and carbonyl-C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 67 ,
R 67 being identical or different and being hydroxyl, formyl, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, nitroso, amino, phenyl, C 1 -C 5 -alkyl or C 1 -C 5 -alkoxy radical, or it being possible for the radicals R 63 -R 66 , in pairs, to be linked to give a ring [CR 68 R 69 --] m , where m is an integer and denotes a value of 1 to 4, or linked to give a ring [CR 70 ═CR 71 ] n , where n is an integer and denotes a value of 1 to 3, and
R 68 , R 69 , R 70 and R 71 being identical or different and having the meanings mentioned for R 63 to R 66 .
Aromatic alcohols are preferably to be understood as meaning phenols or higher-condensed phenol derivatives.
Preferred as mediators are compounds of the general formula XXVI or XXVII whose synthesis can be based on the nitrosization of substituted phenols. Examples of such compounds are 2-nitrosophenol, 3-methyl-6-nitrosophenol,
2-methyl-6-nitrosophenol, 4-methyl-6-nitrosophenol, 3-ethyl-6-nitrosophenol, 2-ethyl-6-nitrosophenol,
4-ethyl-6-nitrosophenol, 4-isopropyl-6-nitrosophenol,
4-tert-butyl-6-nitrosophenol, 2-phenyl-6-nitrosophenol,
2-benzyl-6-nitrosophenol, 4-benzyl-6-nitrosophenol,
2-hydroxy-3-nitrosobenzyl alcohol, 2-hydroxy-3-nitrosobenzoic acid, 4-hydroxy-3-nitrosobenzoic acid,
2-methoxy-6-nitrosophenol, 3,4-dimethyl-6-nitrosophenol,
2,4-dimethyl-6-nitrosophenol, 3,5-dimethyl-6-nitrosophenol, 2,5-dimethyl-6-nitrosophenol, 2-nitrosoresorcin,
4-nitrosoresorcin, 2-nitrosoorcin, 2-nitrosophloroglucine and 4-nitrosopyrogallol, 4-nitroso-3-hydroxyaniline, 4-nitro-2-nitrosophenol.
Furthermore preferred as mediators are o-nitroso derivatives of higher-condensed aromatic alcohols. Examples of such compounds are 2-nitroso-1-naphthol, 1-methyl-3-nitroso-2-naphthol and 9-hydroxy-10-nitrosophenanthrene.
Especially preferred as mediators are 1-nitroso-2-naphthol, 1-nitroso-2-naphthol-3,6-disulfonic acid, 2-nitroso-1-naphthol-4-sulfonic acid, 2,4-dinitroso-1,3-dihydroxybenzene, and esters, ethers or salts of the compounds mentioned.
The mediator can furthermore be selected from the group consisting of hydroxypyridines, aminopyridines, hydroxyquinolines, aminoquinolines, hydroxyisoquinolines, aminoisoquinolines, with the nitroso or mercapto substituents which are in the ortho- or para-positions relative to the hydroxyl or amino groups, tautomers of the compounds mentioned, and their salts, ethers and esters.
Preferred as mediators are compounds of the general formula (XXVIII), (XXIX) or (XXX) ##STR19## and tautomers, salts, ethers or esters of the compounds mentioned, where, in formulae XXVIII, XXIX and XX, two radicals R 72 which are in the ortho- or para-position relative to each other are the hydroxyl and nitroso radical or hydroxyl and mercapto radical or nitroso radical and amino radical
and the remaining radicals R 72 are identical or different are are selected from the group consisting of hydrogen, halogen, hydroxyl, mercapto, formyl, cyano, carbamoyl, carboxyl radical, ester and salt of the carboxyl radical, sulfono radical, ester and salt of the sulfono radical, sulfamoyl, nitro, nitroso, amino, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, carbonyl-C 1 -C 6 -alkyl, phospho, phosphono and phosphonooxy radical, ester and salt of the phosphonooxy radical, and
it being possible for carbamoyl, sulfamoyl, amino, mercapto and phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 73 ,
and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl and carbonyl-C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 73 ,
R 73 being identical or different and being hydroxyl, formyl, cyano, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, nitroso, amino, phenyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy radical or C 1 -C 5 -alkylcarbonyl radical and
it being possible for in each case two radicals R 72 or two radicals R 73 or R 72 and R 73 , in pairs, to be linked via a bridge [--CR 74 R 75 --] m where m equals 1, 2, 3 or 4 and R 3 and R 4 are identical or different and are a carboxyl radical, ester or salt of the carboxyl radical, phenyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy radical or C 1 -C 5 -alkylcarbonyl radical and
it being possible for one or more nonadjacent groups [--CR 74 R 75 --] to be replaced by oxygen, sulfur or by an imino radical which is optionally substituted by C 1 -C 5 -alkyl, and it being possible for two adjacent groups [--CR 74 R 75 --] to be replaced by a group [--CR 74 ═R --].
Especially preferred as mediators are compounds of the general formula (XXVIII) or (XXIX) and their tautomers, salts, ethers or esters, where, in formulae (XXVIII) and (XXIX) especially preferred meanings of two radicals R 72 in the ortho-position relative to each other are the hydroxyl and nitroso radical or hydroxyl and mercapto radical or nitroso radical and amino radical and the remaining radicals R 72 are identical or different and are selected from the group consisting of hydrogen, hydroxyl, mercapto, formyl, carbamoyl, carboxyl radical, ester and salt of the carboxyl radical, sulfono radical, ester and salt of the sulfono radical, sulfamoyl, nitro, nitroso, amino, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 5 -carbonyl, carbonyl-C 1 -C 6 -alkyl, phospho, phosphono and phosphonooxy radical, ester and salt of the phosphonooxy radical,
it being possible for carbamoyl, sulfamoyl, amino, mercapto and phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 73 and
it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 5 -carbonyl and carbonyl-C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 73 ,
R 73 having the meanings which have already been mentioned and
it being possible for in each case two radicals R 73 , in pairs, to be linked via a bridge [--CR 74 R 75 --] m where m equals 2, 3 or 4 and
R 74 and R 75 having the meanings which have already been mentioned and
it being possible for one or more nonadjacent groups [--CR 74 R 75 --] to be replaced by oxygen or by an imino radical which is optionally substituted by C 1 -C 5 -alkyl.
Examples of compounds which can be employed as mediators are 2,6-dihydroxy-3-nitrosopyridine, 2,3-dihydroxy-4-nitrosopyridine,
2,6-dihydroxy-3-nitrosopyridine-4-carboxylic acid,
2,4-dihydroxy-3-nitrosopyridine, 3-hydroxy-2-mercaptopyridine, 2-hydroxy-3-mercaptopyridine, 2,6-diamino-3-nitrosopyridine, 2,6-diamino-3-nitrosopyridine-4-carboxylic acid,
2-hydroxy-3-nitrosopyridine, 3-hydroxy-2-nitrosopyridine,
2-mercapto-3-nitrosopyridine, 3-mercapto-2-nitrosopyridine,
2-amino-3-nitrosopyridine, 3-amino-2-nitrosopyridine,
2,4-dihydroxy-3-nitrosoquinoline, 8-hydroxy-5-nitrosoquinoline,
2,3-dihydroxy-4-nitrosoquinoline, 3-hydroxy-4-nitrosoisoquinoline, 4-hydroxy-3-nitrosoisoquinoline, 8-hydroxy-5-nitrosoisoquinoline and tautomers of these compounds.
Preferred as mediators are 2,6-dihydroxy-3-nitrosopyridine, 2,6-diamino-3-nitrosopyridine, 2,6-dihydroxy-3-nitrosopyridine-4-carboxylic acid, 2,4-dihydroxy-3-nitrosopyridine, 2-hydroxy-3-mercaptopyridine, 2-mercapto-3-pyridinol, 2,4-dihydroxy-3-nitrosoquinoline, 8-hydroxy-5-nitrosoquinoline, 2,3-dihydroxy-4-nitrosoquinoline and tautomers of these compounds.
The mediator can furthermore be selected from the group of the stable nitroxyl radicals (nitroxides), i.e. these free radicals can be obtained, characterized and stored in pure form.
Mediators which are preferably employed in this case are compounds of the general formula (XXXI), (XXXII) or (XXXIII) ##STR20## where Ar is a monovalent homo- or heteroaromatic mono- or binuclear radical, and
it being possible for this aromatic radical to be substituted by one or more, identical or different radicals R 77 selected from the group consisting of halogen, formyl, cyano, carbamoyl, carboxyl, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, nitroso, amino, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, carbonyl-C 1 -C 6 -alkyl, phospho, phosphono and phosphonooxy radical, ester or salt of the phosphonooxy radical, and
it being possible for phenyl, carbamoyl and sulfamoyl radicals to be unsubstituted or mono- or polysubstituted by a radical R 78 , it being possible for the amino radical to be mono- or disubstituted by R 78 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl and carbonyl-C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 78 ,
it being possible for R 78 to be present once or more than once, R 78 being identical or different and being hydroxyl, formyl, cyano, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, nitroso, amino, phenyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy or C 1 -C 5 -alkylcarbonyl radical and
R 76 is identical or different and is halogen, hydroxyl, mercapto, formyl, cyano, carbamoyl, carboxyl radical, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, nitroso, amino, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, carbonyl-C 1 -C 6 -alkyl, phospho, phosphono, phosphonooxy radical, ester or salt of the phosphonooxy radical
and, in the case of bicyclic stable nitroxyl radicals (structure XXXIII), R 76 can also be hydrogen, and
it being possible for carbamoyl, sulfamoyl, amino, mercapto and phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 79 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl and carbonyl-C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 79 , R 79 being identical or different and being hydroxyl, formyl, cyano, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, nitroso, amino, phenyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy radical or C 1 -C 5 -alkylcarbonyl radical, and it being possible for in each case two radicals R 78 or R 79 , in pairs, to be linked via a bridge [--CR 80 R 81 --] m where m equals 0, 1, 2, 3 or 4, and
R 80 and R 81 being identical or different and being halogen, carboxyl radical, ester or salt of the carboxyl radical, carbamoyl, sulfamoyl, phenyl, benzoyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy radical or C 1 -C 5 -alkylcarbonyl radical, and it being possible for one or more nonadjacent groups [--CR 80 R 81 --] to be replaced by oxygen, sulfur or by an imino radical which is optionally substituted by C 1 -C 5 -alkyl, and it being possible for two adjacent groups [--CR 80 R 81 --] to be replaced by a group [--CR 80 ═CR 81 --], [--CR 80 ═N--] or [--CR 80 ═N(O)--].
Especially preferred as mediators are nitroxyl radicals of the general formulae (XXXIV) and (XXXV), ##STR21## where R 82 is identical or different and is phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl or carbonyl-C 1 -C 6 -alkyl,
it being possible for phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 84 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl and carbonyl-C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 84 ,
it being possible for R 84 to be present once or more than once, R 84 being identical or different and being hydroxyl, formyl, carboxyl radical, ester or salt o the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, nitroso, amino, phenyl, benzoyl, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy radical or C 1 -C 5 -alkylcarbonyl radical and
R 83 is identical or different and is hydrogen, hydroxyl, mercapto, formyl, cyano, carbamoyl, carboxyl radical, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, nitroso, amino, phenyl, aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl, carbonyl-C 1 -C 6 -alkyl, phospho, phosphono or phosphonooxy radical, ester or salt of the phosphonooxy radical,
it being possible for carbamoyl, sulfamoyl, amino, mercapto and phenyl radicals to be unsubstituted or to be mono- or polysubstituted by a radical R 78 and it being possible for the aryl-C 1 -C 5 -alkyl, C 1 -C 12 -alkyl, C 1 -C 5 -alkoxy, C 1 -C 10 -carbonyl and carbonyl-C 1 -C 6 -alkyl radicals to be saturated or unsaturated, branched or unbranched and to be mono- or polysubstituted by a radical R 78 and it being possible for a [--CR 83 CR 83 --] group to be replaced by oxygen, an imino radical which is optionally substituted by C 1 -C 5 -alkyl, a (hydroxy)imino radical, a carbonyl function or by a vinylidene function which is optionally mono- or disubstituted by R 78 and it being possible for two adjacent groups [--CR 83 R 83 --] to be replaced by a group [--CR 83 ═CR 83 --] or [--CR ═N--] or [--CR 83 ═N(O)--].
Examples of compounds which can be employed as mediators are
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO),
4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-oxo-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-acetamido-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-(ethoxyfluorophosphinyloxy)-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-(isothiocyanato)-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-maleimido-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-(4-nitrobenzoyloxy)-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-(phosphonooxy)-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-cyano-2,2,6,6-tetramethyl-1-piperidinyloxy,
3-carbamoyl-2,2,5,5-tetramethyl-3-pyrroline-1-oxyl,
4-phenyl-2,2,5,5-tetramethyl-3-imidazolin-1-yloxy-3-oxide,
4-carbamoyl-2,2,5,5-tetramethyl-3-imidazolin-1-yl oxy-3-oxide,
4-phenacetylidene-2,2,5,5-tetramethylimidazolin-1-yloxy,
3-(aminomethyl)-2,2,5,5-tetramethyl-N-pyrrolidinyloxy,
3-carbamoyl-2,2,5,5-tetramethyl-N-pyrrolidinyloxy,
3-carboxy-2,2,5,5-tetramethyl-N-pyrrolidinyloxy,
3-cyano-2,2,5,5-tetramethyl-N-pyrrolidinyloxy,
3-maleimido-2,2,5,5-tetramethyl-N-pyrrolidinyloxy,
3-(4-nitrophenoxycarbonyl)-2,2,5,5-tetramethyl-N-pyrrolidinyloxy.
Preferred mediators are
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO),
4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-oxo-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-acetamido-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-(isothiocyanato)-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-maleimido-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-(4-nitrobenzoyloxy)-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-(phosphonooxy)-2,2,6,6-tetramethyl-1-piperidinyloxy,
4-cyano-2,2,6,6-tetramethyl-1-piperidinyloxy,
3-carbamoyl-2,2,5,5-tetramethyl-1-pyrrolinidinyloxy,
4-phenyl-2,2,5-5-tetramethyl-3-imidazolin-1-yloxy-3-oxide,
4-carbamoyl-2,2,5-5-tetramethyl-3-imidazolin-1-yloxy-3-oxide,
4-phenacetylidene-2,2,5,5-tetramethyl-1-imidazolidinyloxy.
Particularly preferred as mediators are 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy.
Especially preferred mediators are selected from the group consisting of N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, violuric acid, N-hydroxyacetanilide, nitrosonaphthols, nitrosopyridinols and their derivatives which have been given above.
Very especially preferred are
3-amino-N-hydroxyphthalimide, 4-amino-N-hydroxyphthalimide, N-hydroxyphthalimide, 3-hydroxy-N-hydroxyphthalimide, 3-methoxy-N-hydroxyphthalimide,
3,4-dimethoxy-N-hydroxyphthalimide,
4,5-dimethoxy-N-hydroxyphthalimide,
3,6-dihydroxy-N-hydroxyphthalimide,
3,6-dimethoxy-N-hydroxyphthalimide,
3-methyl-N-hydroxyphthalimide,
4-methyl-N-hydroxyphthalimide,
3,4-dimethyl-N-hydroxyphthalimide,
3,5-dimethyl-N-hydroxyphthalimide,
3,6-dimethyl-N-hydroxyphthalimide,
3-isopropyl-6-methyl-N-hydroxyphthalimide,
3-nitro-N-hydroxyphthalimide, 4-nitro-N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, violuric acid, N-hydroxyacetanilide, 3-nitrosoquinoline-2,4-diol,
2,4-dihydroxy-3-nitrosopyridine, 2,6-dihydroxy-3-nitrosopyridine, 2,4-dinitroso-1,3-dihydroxybenzene, 2-nitroso-1-naphthol-3-sulfonic acid and 1-nitroso-2-naphthol-3,6-disulfonic acid.
The oxidation is preferably carried out in the presence of 0.01 to 10 equivalents, preferably 0.05 to 1 equivalent, especially preferably 0.1 to 0.5 equivalent of one or more of the mediators described, preferably with one or two mediators, especially preferably with one mediator in water.
If appropriate, this is done with addition of 1 to 90 percent by weight, preferably 5 to 30 percent by weight, of a solvent which is at least partially miscible with water. It is preferred to add 1 to 3 organic solvents which are miscible with water as cosolvents. Examples of organic solvents which are miscible with water are ethanol, methanol, isopropanol, ethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, acetone, acetonitrile, acetamide, tetrahydrofuran, dioxane, DMSO, DMF, sulfolane, methyl acetate, ethyl acetate, formic acid, acetic acid or propionic acid, or any mixtures of these.
The pH of the solution is preferably 2 to 8, especially preferably 4 to 5.
The reactions are preferably carried out at temperatures between 5 and 70° C., especially preferably 35-50° C., and the reaction times are preferably 2 to 100 hours, especially preferably 5 to 50 hours.
Oxidants which are preferably employed are air, oxygen, hydrogen peroxide, organic peroxides, peracids, perborates or persulfates, in each case in combination with enzymes or metal oxides.
The term enzyme for the purposes of the invention also includes enzymatically active proteins or peptides or prosthetic groups of enzymes. Enzymes which can be employed in the multi-component system according to the invention are oxidoreductases of classes 1.1.1 to 1.97 in accordance with the International Enzyme Nomenclature, Committee of the International Union of Biochemistry and Molecular Biology (Enzyme Nomenclature, Academic Press, Inc., 1992, pp. 24-154).
Enzymes of the classes mentioned below are preferably employed: Enzymes of class 1.1, which embrace all dehydrogenases which act on primary, secondary alcohols and semiacetals and which have, as acceptors NAD + or NADP + (subclass 1.1.1), cytochromes (1.1.2), oxygen (O 2 ) (1.1.3), disulfides (1.1.4), quinones (1.1.5) or which have other acceptors (1.1.99).
Especially preferred amongst this class are the enzymes of class 1.1.5 with quinones as the acceptors and the enzymes of class 1.1.3 with oxygen as the acceptor.
Particularly preferred amongst this class is cellobiose: quinone-1-oxidoreductase (1.1.5.1).
Furthermore preferred are enzymes of class 1.2. This enzyme class embraces those enzymes which oxidize aldehydes to the corresponding acids or oxo groups. The acceptors can be NAD + , NADP + (1.2.1), cytochromes (1.2.2), oxygen (1.2.3), sulfides (1.2.4), iron-sulfur-proteins (1.2.5) or other acceptors (1.2.99).
Especially preferred here are the enzymes of group (1.2.3).with oxygen as the acceptor.
Furthermore preferred are enzymes of class 1.3.
In this class there are compiled enzymes which act on CH--CH groups of the donor.
The corresponding acceptors are NAD + , NADP + (1.3.1), cytochromes (1.3.2), oxygen (1.3.3), quinones or related compounds (1.3.5), iron-sulfur-proteins (1.3.7) or other acceptors (1.3.99).
Especially preferred is bilirubin oxidase (1.3.3.5).
Again, the enzymes of class (1.3.3) with oxygen as the acceptor and (1.3.5) with quinones etc. as the acceptor are especially preferred here.
Furthermore preferred are enzymes of class 1.4, which act on CH--NH 2 groups of the donor.
The corresponding acceptors are NAD + , NADP + (1.4.1), cytochromes (1.4.2), oxygen (1.4.3), disulfides (1.4.4), iron-sulfur-proteins (1.4.7) or other acceptors (1.4.99).
Here too, especially preferred are enzymes of class 1.4.3 with oxygen as the acceptor.
Furthermore preferred are enzymes of class 1.5, which act on CH--NH groups of the donor. The corresponding acceptors are NAD + , NADP + (1.5.1), oxygen (1.5.3), disulfides (1.5.4), quinones (1.5.5) or other acceptors (1.5.99).
Again, especially preferred here are enzymes with oxygen (O 2 ) (1.5.3) and with quinones (1.5.5) as the acceptors.
Furthermore preferred are enzymes of class 1.6, which act on NADH or NADPH.
Here, the acceptors are NADP + (1.6.1), hem proteins (1.6.2), disulfides (1.6.4), quinones (1.6.5), NO 2 groups (1.6.6) and a flavine (1.6.8) or some other acceptors (1.6.99).
Especially preferred here are enzymes of class 1.6.5 with quinones as the acceptors.
Furthermore preferred are enzymes of class 1.7, which act on other NO 2 compounds as donors and which have cytochromes (1.7.2), oxygen (O 2 ) (1.7.3), iron-sulfur-proteins (1.7.7) or others (1.7.99) as the acceptors.
Especially preferred here is class 1.7.3 with oxygen as the acceptor.
Furthermore preferred are enzymes of class 1.8, which act on sulfur groups as donors and which have NAD + , NADP + (1.8.1), cytochromes (1.8.2), oxygen (O 2 ) (1.8.3), disulfides (1.8.4), quinones (1.8.5), iron-sulfur-proteins (1.8.7) or others (1.8.99) as the acceptors.
Especially preferred is class 1.8.3 with oxygen (O 2 ) and (1.8.5) with quinones as the acceptors.
Furthermnore preferred are enzymes of class 1.9, which act on hem groups as donors and which have oxygen (O 2 ) (1.9.3), NO 2 compounds (1.9.6) and others (1.9.99) as the acceptors.
Especially preferred here is group 1.9.3 with oxygen (O 2 ) as the acceptor (cytochrome oxidases).
Furthermore preferred are enzymes of class 1.12, which act on hydrogen as the donor.
The acceptors are NAD + or NADP + (1.12.1) or others (1.12.99).
Furthermore preferred are enzymes of class 1.13 and 1.14 (oxygenases).
Furthermore preferred enzymes are those of class 1.15, which act on superoxide free radicals as the acceptors.
Especially preferred here is superoxide dismutase (1.15.1.1).
Furthermore preferred are enzymes of class 1.16. NAD + or NADP + (1.16.1) or oxygen (O 2 ) (1.16.3) act as the acceptors.
Especially preferred here are enzymes of class 1.16.3.1 (ferroxidase, e.g. ceruloplasmin).
Furthermore preferred enzymes are those which belong to group 1.17 (acts on CH 2 groups, which are oxidized to --CHOH--), 1.18 (acts on reduce ferredoxin as donor), 1.19 (acts on reduced flavodoxin as donor) and 1.97 (other oxidoreductases).
Furthermore especially preferred are the enzymes of group 1.11., which act on a peroxide as the acceptor. This single subclass (1.11.1) contains the peroxidases.
Especially preferred here are cytochrome c peroxidases (1.11.1.5), catalase (1.11.1.6), peroxidase (1.11.1.7), iodide peroxidase (1.11.1.8), glutathione peroxidase (1.11.1.9), chloride peroxidase (1.11.1.10), L-ascorbate peroxidase (1.11.1.11), phospholipid hydroperoxide glutathione peroxidase (1.11.1.12), manganese peroxidase (1.12.1.13) and diarylpropane peroxidase (ligninase, lignin peroxidase) (1.11.1.14).
Very especially preferred are enzymes of class 1.10, which act on biphenols and related compounds. They catalyze the oxidation of biphenols and ascorbates. NAD + , NADP + (1.10.1), cytochromes (1.10.2), oxygen (1.10.3) or others (1.10.99) act as the acceptors.
Amongst these, in turn, especially preferred enzymes are those of class 1.10.3 with oxygen (O 2 ) as the acceptor.
Preferred amongst the enzymes of his class are the enzymes catechol oxidase (tyrosinase) (1.10.3.1), L-ascorbate oxidase (1.10.3.3), o-aminophenol oxidase (1.10.3.4) and laccase (benzenediol: oxygen oxidoreductase) (1.10.3.2), the laccases (benzenediol: oxygen oxidoreductase) (1.10.3.2) being particularly preferred.
The abovementioned enzymes are commercially available or can be obtained by standard processes. Organisms which are suitable for producing the enzymes are, for example, plants, animal cells, bacteria and fungi. In principle, naturally occurring and genetically altered organisms may be enzyme producers. Equally, parts of single- or many-celled organisms are conceivable as enzyme producers, above all cell cultures.
Examples of organisms which are used for the particularly preferred enzymes, such as those from group 1.11.1, but mainly 1.10.3, and in particular for the production of laccases are fungi that cause white rot such as Pleurotus, Phlebia and Trametes.
Preferred amongst the metal oxides employed as oxidants are those with a solubility of less than 1 g/l in the reaction medium.
The following are preferred: bismuth(III) oxide, iridium(III) oxide, cerium(IV) oxide, coalt(II) oxide, cobalt(III) oxide, iron(III) oxide, manganese(IV) oxide, tin(IV) oxide, niobium(V) oxide, antimony(V) oxide, indium(III) oxide, mercury(II) oxide, lead(IV) oxide, silver(I) oxide, copper(II) oxide, palladium(II) oxide.
The following are especially preferred: lead(IV) oxide, manganese(IV) oxide, silver(I) oxide, copper(II) oxide, palladium(II) oxide.
The process according to the invention allows aromatic or heteroaromatic aldehydes and ketones to be prepared from the corresponding methyl or methylene compounds under mild reaction conditions.
The reaction is preferably carried out in water, if appropriate with addition of a cosolvent as solubilizer, and is therefore especially inexpensive.
The reaction solution is worked up in a simple manner, for example by extraction.
The mediators used can be employed catalytically. Aromatics which are substituted by electron donors react especially fast. The high selectivity is shown with reference to the oxidation of o-xylene. Here, the first methyl group is oxidized much faster, which allows o-tolyl aldehyde to be synthesized.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Other objects and features of the present invention will become apparent from the following detailed description considered in connection with the accompanying examples. It should be understood, however, that this is designed for the purpose of illustration only and not as a definition of the limits of the invention.
EXAMPLE 1
22 ml of a dipotassium hydrogen phosphate/citric acid buffer solution of pH 4.5 (prepared by titrating a 0.2 M potassium dihydrogen phosphate solution with a 0.1 M citric acid solution and diluting to 1/4) were treated at 45° C. with 243 mg (1.60 mmol) of 3,4-dimethoxytoluene in 1 ml of ethanol. 0.180 mmol of a mediator (Table 1) was added with stirring. After approx. 10 minutes, the mixture was treated with 5 ml of an aqueous solution of 2 mg/ml laccase from Trametes versicolor (specific activity: approx. 18 IU/mg, defined with ABTS as substrate). After a reaction time of 22 hours with exposure to air, the reaction solution was extracted with chloroform and examined by N spectroscopy and gas chromatography. Yields of 3,4-dimethoxybenzaldehyde and 3,4-dimethoxybenzyl alcohol, see Table 1.
TABLE 1______________________________________Conversion of 3,4-dimethoxytoluene with laccase and a variety of mediators (cosolvent: ethanol) Aldehyde Alcohol Mediator (0.11 equ.) (%) (%)______________________________________1-hydroxy-1H-benzotriazole 85 14 N-hydroxyphthalimide (=HPI) 9 4 3,6-dihydroxy-HPI 0.2 0.5 3,4-dimethoxy-HPI 26 7 4,5-dimethoxy-HPI 27 6 3,6-dimethoxy-HPI 17 4 315-dimethyl-HPI 33 7 3-isopropyl-6-methyl-HPI 90 10 3-methyl-HPI 81 7 4-methyl-HPI 84 11 3-amino-HPI 91 7______________________________________
EXAMPLE 2
195 mg (1.60 mmol) of 4-methylanisole were reacted analogously to Example 1 in the presence of 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide. After a reaction time of 22 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy and gas chromatography. Yield 61% of 4-methoxybenzaldehyde (approx. 90%, based on conversion).
EXAMPLE 3
195 mg (1.60 mmol) of 4-methylanisole were reacted analogously to Example 1 in the presence of 24.3 mg (0.180 mmol) of 1-hydroxy-1H-benzotriazole. After a reaction time of 22 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yield 48% of 4-methoxybenzaldehyde (approx. 90%, based on conversion).
EXAMPLE 4
172 mg (1.60 mmol) of 4-toluidine were reacted analogously to Example 1 in the presence of 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide. After a reaction time of 22 hours, the reaction solution was brought to pH 8 with 2M NaOH, extracted with chloroform and examined by NMR spectroscopy. Yield 62% of 4-aminobenzaldehyde.
EXAMPLE 5
170 mg (1.60 mmol) of o-xylene were reacted analogously to Example 1 in the presence of 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide. After a reaction time of 4 hours and 18 hours, a further 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide were added in each case, and, after a total of 30 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yield 30% of 2-methylbenza ehyde and 7% of 2-methylbenzyl alcohol.
EXAMPLE 6
188 mg (1.60 mmol) of 4-tolunitrile were reacted analogously to Example 1 in the presence of 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide. After a reaction time of 22 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yield 10%.
EXAMPLE 7
212 mg (1.60 mmol) of 1,2,3,4-tetrahydronaphthalene in 1.1 ml of acetone were reacted analogously to Example 1 with 71 mg (0.53 mmol) of 1-hydroxy-1H-benzotriazole in 3 ml of acetone and 15 ml of an aqueous solution of 2 mg/ml laccase from Trametes versicolor. After a reaction time of 24 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yield 42% of 1-tetralone and 6% of 5-hydroxytetralin (approx. 90% yield of 1-tetralone based on conversion).
EXAMPLE 8
1-ethylbenzene was reacted analogously to Example 1 with 0.22 equivalent of 1-hydroxy-1H-benzotriazole and 10 ml of a solution of 2 mg/ml laccase. After a reaction time of 24 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yield 42% of acetophenone, 34% of 1-phenylethanol, 24% of unreacted acetophenone.
EXAMPLE 9
259 mg (1.60 mmol) of 6-methoxy-1,2,3,4-tetrahydronaphthalene in 1.1 ml of solvent were reacted analogously to Example 1 with a variety of mediators and laccase (see Table 2). After a reaction time of 24 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yields of 6-methoxy-1-tetralone and 6-methoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene, see Table 2.
TABLE 2______________________________________Oxidation of 6-methoxy-1,2,3,4-tetrahydro- naphthalene to 6-methoxy-1-tetralone (HOBT: 1-hydroxy-1H- benzotriazole, 4-methyl-HPI: 4-methyl-N-hydroxyphthali-mide) Laccase Mediator (equiv., cosolvent) (U/mmol) %1 %2______________________________________HOBT (0.11, ethanol) 113 29 7 HOBT (0.22, ethanol) 113 52 13 HOBT (0.33, ethanol) 113 60 12 HOBT (0.11, ethanol) 339 51 11 HOBT (0.33, ethanol) 339 95 2 HOBT (0.11, ethanol).sup.a) 113.sup.a) 39 3 HOBT (0.11, acetone) 113 35 7 HOBT (0.22, acetone).sup.b) 226.sup.b) 51.sup.c) 8 HPI (0.22/acetone)b) 226.sup.b) 21.sup.d) 8 4-methyl-HPI (0.11, ethanol) 113 8 8 4-methyl-HPI (0.22, ethanol) 113 32 8 4-methyl-HPI (0.11, ethanol) 339 59 5 4-methyl-HPI (0.33, ethanol) 339 92 3 4-methyl-HPI (0.11, ethanol).sup.a) 113.sup.a' 36 4 4-methyl-HPI (0.11, acetone) 113 31 6 3-amino-HPI (0.11, ethanol) 113 37 6 3-amino-HPI (0.22, ethanol) 113 32 10 3-N,N-dimethylamino-HPI (0.11, ethano1) 113 43 13______________________________________ .sup.a) Addition in 3 portions, .sup.b) addition in 5 portions, .sup.c) 24% of unreacted 1,2,3,4tetrahydronaphthalene, .sup.d) *58% of unreacted 1,2,3,4tetrahydronaphthalene.
EXAMPLE 10
22 ml of a dipotassium hydrogen phosphate/citric acid buffer solution of pH 4.5 (prepared by titrating a 0.2 M potassium dihydrogen phosphate solution with a 0.1 M citric acid solution and diluting to 1/4) were treated at 45° C. with 243 mg (1.60 mmol) of 3,4-dimethoxytoluene in 1 ml of ethanol. 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide were added with stirring. After approx. 10 minutes, 950 mg (3.97 mmol) of lead dioxide were added, and the mixture was stirred for 22 hours at 45° C. in a sealed flask. HPLC analysis of the reaction mixture revealed 9% of 3,4-dimethoxybenzaldehyde and 28% of 3,4-dimethoxybenzyl alcohol.
EXAMPLE 11
243 mg (1.60 mmol) of 3,4-dimethoxytoluene were reacted analogously to Example 8 with 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide and 346 mg (3.98 mmol) of manganese dioxide. HPLC analysis after a reaction time of 22 hours revealed 13% of 3,4-dimethoxybenzaldehyde and 19% of 3,4-dimethoxybenzyl alcohol.
EXAMPLE 12
Following the protocol of Potthast et al. (J. Org. Chem. 1995, 60, 4320), 13.7 mg (0.100 mmol) of 4-nitrotoluene in 0.1 ml of THF were added to a solution of 0.55 mg (0.010 mmol) of ABTS in 0.5 ml ot acetate buffer, and the stirred mixture was flushed for 1 minute with oxygen. After addition of 0.10 ml of laccase stock solution (Mercian, laccase activity 95 IU, based on the conversion of 4-hydroxymandelic acid as substrate), the reaction mixture turned deep bluish-green and was stirred for 23 hours at room temperature. The reaction mixture was subsequently again flushed for 1 minute with oxygen and the reaction was continued for 8 hours at 40° C., and this procedure was repeated twice more. Besides unreacted 4-nitrotoluene, 4-nitrobenzaldehyde was no longer detectable when examining the reaction solution by gas chromatography (detection limit approx. 0.02%).
EXAMPLE 13
Following the protocol of Potthast et al. (J. Org. Chem. 1995, 60, 4320), 15.2 mg (0.100 mmol) of 3,4-dimethoxytoluene in 0.1 ml of THF were added to a solution of 0.55 mg (0.010 mmol) of ABTS in 0.5 ml of acetate buffer, analogously to Example 8, and the stirred mixture was flushed for 1 minute with oxygen. After addition of 0.10 ml of laccase stock solution (see Example 10), the reaction mixture turned deep bluish-green and was stirred for 8 hours at room temperature. The reaction mixture was subsequently again flushed for 1 minute with oxygen and the reaction was continued for 16 hours at room temperature. me mixture was again flush with oxygen and the reaction was continued for 7 hours at 40° C. Examination of the reaction solution by gas chromatography revealed 0.3% of 3,4-dimethoxybenzaldehyde.
While several embodiments of the present invention have been shown and described, it is to be understood that many changes and modifications may be made thereunto without departing from the spirit and scope of the invention as defined in the appended claims.
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A process for the preparation of vinyl, alkynyl or aryl aldehydes or vinyl, alkynyl or aryl ketones includes reacting vinyl-, alkynyl- and aryl- and -methylene compounds with the aid of a mediator and an oxidant, wherein the mediator is selected from the group of the aliphatic, heterocyclic or aromatic NO or NOH containing compounds.
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This application is a division of application Ser. No. 09/657,741, filed on Sep. 8, 2000, now U.S. Pat. No. 6,537,476.
BACKGROUND
Applications exist for dispensing medications by way of inhaler devices. Such devices long have been popular for use by persons with asthma to deliver vapor medications stored under pressure, through a chamber, and ultimately, to an inhaler which is placed in the mouth of the person requiring the medication. The medicine which is dispersed in asthma inhalers, however, is vaporized liquid, which is placed in a pressure dispenser associated with the inhaler. Whenever a dosage of medicine is to be delivered, a valve is momentarily opened to dispense and vaporize the stored liquid for inhalation by the user.
In recent years, experimentation has been undertaken for delivering powdered medicine by way of an inhaler. Particularly promising is the development of insulin powder which may be inhaled, thereby eliminating the need for injected insulin and all of the problems which are attendant with medications which must be injected at frequent intervals. For delivering powdered medication such as insulin powder, the inhaler device must be designed to blow a stream of compressed air through the powder, creating a cloud of tiny medication particles which then may be inhaled from the device.
The U.S. Pat. No. 5,287,850 to Haber is directed to a powdered pharmaceutical inhaler mechanism. The device of this patent delivers pressurized air through a coiled tube for dispersing and driving powdered pharmaceutical into the mouthpiece for inhalation by the user. Different parts of the mechanism shown in this patent are designed to be moved from a loading position to a delivery position; and this includes the coiled tube which interconnects these parts. The movement of the tube in this device, however, is quite limited, as is readily apparent from an examination of the device shown in the patent.
For inhaler mechanisms where there is a manual pressurization of a charge of air, different parts of the mechanism need to be moved toward and away from one another a greater distance than the parts of the Haber patent. Typically, such mechanisms require movement of from one-half inch to 1½ inches in order to effect the desired charging and cocking of the mechanism. In such manual pressurization mechanisms, it is necessary to utilize a flexible tube to interconnect the charged air with the delivery portion. This tube must be capable of handling the air pressure charge, as well as extension and retraction as the device is utilized. Because there is a relatively long distance of travel between the parts in the various stages of operation, it has been found that a sufficiently long straight length of plastic tubing tends to bend and rub against other internal parts. This rubbing ultimately causes weakness in the wall of the tube, resulting in failure of the device. Because of the relatively large distance of travel in such a manual charging and cocking mechanism, it also is possible to crimp or kink the tube, which also leads to incomplete or ineffective delivery of the medication, and a failure of operation of the device.
It is desirable to provide a machine and method for forming a thermoplastic tube, with a uniform cross-sectional thickness throughout its length, as a helical spring, which can be extended and released to its thermoset, coiled, biased condition repeatedly for use in manually charged powdered medication delivery systems.
SUMMARY OF THE INVENTION
It is an object of this invention to provide a method for forming a helical coil in a length of hollow cylindrical plastic tubing.
It is another object of this invention to provide a method for forming a helical coil in a length of hollow cylindrical plastic tubing, where the wall thickness of the tubing is uniform throughout its length, including the helical coil.
It is an additional object of this invention to provide a machine for forming a helical spring coil in a length of hollow cylindrical thermoplastic tubing.
It is a further object of this invention to provide a method and machine for forming a thermoset spring coil in a length of hollow cylindrical thermoplastic tubing.
In accordance with a preferred embodiment of this invention, a method and machine form a helical coil in a length of hollow cylindrical thermoplastic tubing. This is accomplished by clamping the ends of a predetermined length of plastic tubing between first and second opposed spaced clamping mechanisms, which may be in the form of first and second sections of a mandrel. The clamping mechanisms, or first and second mandrel sections, then are rotated relative to one another and simultaneously moved toward one another to form a helical coil in the tubing. Where first and second mandrel sections are employed, the helical coil is formed around the mandrels as they move toward one another. Once the coil is formed, the region of at least the coil portion of the tubing is heated to the thermosetting temperature of the tubing to heat-form the coil in the tubing. Following the heating to set the coil, the coil and tubing are cooled; and the spring coil tube is released from the machine.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side view of a thermoplastic tube segment, which is formed into a thermoset coil by the machine of the preferred embodiment of the invention;
FIG. 2 is a side view of a completed part made by the machine of the preferred embodiment;
FIG. 3 is a cross-sectional view, taken along the line 3 — 3 of FIG. 2;
FIG. 4 is a perspective view of a preferred embodiment of the invention;
FIG. 5 is an exploded view of a portion of the embodiment shown in FIG. 4;
FIG. 6 is a cross-sectional detail of a portion of the embodiment shown in FIGS. 4 and 5;
FIG. 7 is a cross-sectional view taken along the line 7 — 7 of FIG. 6;
FIG. 8 is an enlarged detail of the portion encircled as 8 ″ in FIG. 6; and
FIG. 9 is an enlarged detail of the portion shown encircled as 9 ″ in FIG. 6 .
DETAILED DESCRIPTION
Reference now should be made to the drawings, in which the same or similar components have the same reference numbers throughout the different figures. FIG. 1 is a side view of a short length of elongated flexible tube or conduit, which is intended to be formed into a coiled spring conduit member designed to interconnect two different parts of a powdered medicine delivery inhaler mechanism.
An inhaler device, in which the tube shown in FIGS. 1, 2 and 3 , is used, is subjected to air pressure of approximately 80 psi when air is released through the dispenser device and the tube 10 . The tube 10 of FIG. 1 is formed from thermoplastic material, which may be extruded and then subsequently heat formed. Initially, extruded tubular material, having the desired internal and external diameters, is cut into the desired length; and segments 14 and 16 , at both ends, are flared by means of heat forming insert mandrels. The manner in which this is accomplished is not important to an understanding of the present invention. It is to be noted, however, that the starting material for use with the machine described subsequently is the tube 10 , shown in FIG. 1, with the enlarged or flared segments 14 and 16 on the ends. The flared segments are selected to have an internal diameter which is greater than the uniform internal diameter of the main body 10 of the tube, for purposes of interconnecting the finished product in an inhaler with a uniform internal diameter airflow passage throughout the length of the entire mechanism, including the portions to which the flared end segments 14 and 16 are attached.
In order to form a substantially single-turn helical coil 12 ; thermoset into the shape shown in FIG. 2, from the straight length of tube 10 of FIG. 1, the machine shown in FIGS. 4 through 9 is employed. This machine is designed to simultaneously produce six thermoset coiled spring tube members of the type shown in FIGS. 2 and 3 with each cycle of operation. The finished product, as shown in FIGS. 2 and 3, is a thermoplastic tube 10 with a uniform cross-sectional thickness throughout its length. The tube is thermoset formed as a helical spring which may be extended and released repeatedly to its thermoset-biased coiled condition, for use in manually-charged, powdered medication delivery systems.
FIG. 4 is a top perspective view of the primary operating components of the machine of the preferred embodiment used to form the product shown in FIG. 2 . Some conventional mechanisms, which may be associated with the machine of FIGS. 4 and 5, have not been shown in order to more clearly present the features which are unique to the operation of the preferred embodiment of the invention.
Basically, the machine includes two spaced-apart parallel mounting blocks 20 and 22 , which are secured to a machine base (not shown) in any suitable manner. The blocks are spaced a uniform distance apart; and each of them includes six aligned, equally spaced support bearings for rotating mandrels. The mandrels, in turn, are supported in a pair of movable, bearing support members 24 and 26 for the blocks 20 and 22 , respectively. Six mandrels 28 extend through bearings 32 in the member 24 ; and a corresponding six mandrels 30 extend through bearings 34 in the mandrel support member 26 .
As shown in both FIGS. 4 and 5, the mandrels 30 also slidably extend through the bearings 36 in the main support block 22 , as well. Similar bearings (not shown) in the support block 20 are used for allowing pivotal rotation of the mandrels 28 in that support block for either or both sets of mandrels 28 and 30 . The mandrel support members 24 and 26 for either or both sets of mandrels 28 and 30 are arranged to be moved toward and away from the blocks 20 and 22 , respectively, through means of a suitable electromechanical system 94 . This is diagrammatically illustrated in FIG. 4, by means of the dotted lines 100 and 102 interconnecting the mandrel support members 24 and 26 with a control and drive motor unit 94 .
In the operation of the machine, at the beginning of each cycle, six pre-formed plastic tube sections of the type shown in FIG. 1 are dropped into aligned slots 62 and 83 , formed on the upper surfaces of opposite sleeves 60 and 82 , respectively, which surround the mandrels 30 and 28 , as shown most clearly in FIG. 6 . One of the pre-formed lengths of tube 10 , with the flared end segments 14 and 16 , is placed in each of these opposing sleeves in the slots on the top of the mandrels 30 and 28 , in each of the six different positions of the six-unit machine shown in FIG. 4 . Each of the different positions are identical; and one of them is diagrammatically illustrated in FIG. 6 .
FIG. 5 illustrates, in an exploded view, the portions of the sleeves and operating parts which are associated with one of the mandrels 30 . It should be noted that each of the mandrels 30 are identical, and that the corresponding parts which are associated with those mandrels are identical. For that reason, only one has been shown in exploded detail. Similarly, the mandrels 28 are surrounded with sleeves and operating collars which are identical to one another, and are identical to the one shown in exploded view in FIG. 5 . In order to avoid cluttering the drawing with unnecessary details, only one of the mandrel and sleeve sets is shown in exploded detail; and only a partial cross section of some of the operating features is shown in FIG. 6 .
When a part 10 is dropped into the slots 62 and 83 , as shown in FIGS. 5 and 6, the flared end rests on a wider flat portion 61 on the sleeve 60 (and a corresponding flat portion on the sleeve 82 ) with the main body of the tube 10 which is located between the end segments 14 and 16 extending through the narrower slot 62 , for example, in the sleeve 60 . An identical construction on all of the other sleeves on both sides of the machine is employed; so that the tube 10 extends through the narrow slots 60 on the machine portion carried by the block 22 , and a similar set of slots 83 carried by the sleeves 82 on the block 20 .
FIG. 7 is a cross-sectional view of this portion of the machine, which illustrates the orientation of the sleeve 82 and its slot 83 , with respect to the mandrels 28 . Again, a similar cross section taken on any of the other sleeves and mandrels, on both sides of the machine, is identical to the one shown in FIG. 7 .
In order to lock the thermoplastic tube section 10 / 14 / 16 into place for effecting a subsequent rotating operation, a second sleeve is provided at each of the mandrel positions. This is a larger sleeve, 90 for the mandrels associated with the block 20 , and 54 for the mandrels 30 associated with the block 22 . The cross-sectional views of FIGS. 6 and 7 illustrate the general orientation of the locking sleeves 90 and 54 with respect to the other parts.
After the tube section 10 of FIG. 1 is placed in the slots on the smaller sleeves 82 and 60 , as described above, the locking sleeves 90 and 54 are rotated to cause the open gap, such as the gap 84 shown in FIGS. 6 and 7, to rotate over and close the opening over the top of the flanges 14 and 16 . The flanges 14 and 16 stick up just slightly above the upper diameter projection of the sleeves 60 and 82 ; so that when this rotation of the sleeves 90 and 54 is effected, a vice-like clamping action is provided to tightly grip the end segments 14 and 16 in place, and hold them against any rotation of the tube 10 during the next cycle of operation of the machine.
To effect the clamping of the end segments 14 and 16 , a rectangular sliding bar assembly, including a pair of spaced-apart horizontal end members 76 and 88 , which are interconnected by elongated side members (not shown) is provided. This rack slides in facing slots 70 and 72 in the support blocks 22 and 20 , respectively, and is operated by the control and drive motor mechanism 94 at the beginning and end of each cycle to reciprocate back and forth, as indicated by the double-ended arrow at the left-hand end of FIG. 4 . Once all of the tubes 10 are in place as described above, the rack 76 / 88 is moved toward the right, as viewed in FIG. 4, to cause six spaced engaging pins 78 , on the right-hand end side of the rack 76 , and a corresponding set of six engaging pins 80 on the left-hand side of the rack, to engage corresponding slots 52 and 42 located, as is most readily apparent in FIGS. 4 and 5, on the lower sides of circular operators 48 and 38 which are fixedly attached for rotation with the sleeves 54 and 90 , respectively. When the rack 76 / 88 moves toward the right, as seen in FIG. 4, the operators 48 associated with the sleeves 54 are rotated clockwise (as viewed in FIG. 5 ); and the operators 38 , associated with the sleeves 90 in the support block 20 , are operated counterclockwise (as viewed in FIG. 4) to rotate over the openings in the ends of the slots 62 and 83 and effect the clamping of the flanges 14 and 16 , as described above. The rack 78 / 88 remains in its rightmost position for the duration of the next portion of the cycle of operation. It should be noted, however, that for the operation just described, the pins 78 and 80 engage the slots 52 and 42 , respectively, to effect the rotation. This causes a second set of slots (located 180° from the slots 42 and 52 engaged by the pins 78 and 72 ) to be rotated into position for subsequent engagement for rotating the assembly back to the starting position, once a complete cycle of operation has taken place. For the purposes of the next portion of the ensuing discussion, however, it should be noted that the rack 78 / 88 moves from the position shown in FIG. 4 toward the right (as shown in FIG. 4 ), as described above, and remains there until it is time to commence a new cycle of operation.
After the flanges 14 and 16 are locked into place, the control and drive motor mechanism 94 commences rotation of the mandrels 30 , through a set of drive shafts, while the mandrels 28 remain in a fixed or non-rotating condition. At the same time, the control and drive motor 94 moves the mandrel support members 24 and 26 toward the blocks 20 and 22 , respectively, in synchronism with the rotational force applied through the drive shafts 96 to the mandrels 30 to cause a coil 12 to be formed in the center of the pre-formed cut length of thermoplastic tubing 10 of FIG. 1 . In FIG. 2 the coil 12 is shown offset from the center, but in reality, the coil 12 will form at the center of the tube 10 because of the uniform wall thickness and strength of the material.
The movement of the mandrel support blocks 24 and 26 , toward one another, is at a rate to accommodate for the reduction in length between the ends of the tube 10 as the coil 12 is formed in it. The coil 12 forms around the path of the mandrels 28 and 30 ; and in fact, as they approach one another, the coil 12 is wound around the mandrels 28 and 30 .
At the end of the rotation to form the coil 12 (chosen to be slightly more than 360° of relative rotation between the mandrels 30 and 28 ), the mandrel ends 29 and 31 engage one another. FIGS. 6, 8 and 9 show details of this portion of the mechanism. The mandrels 28 have a slot 29 formed in their end; and the mandrels 30 have a flat projection 31 formed in the end, which mates with the slot 29 . As a consequence, when the mandrel 30 is moved into engagement with the end of the mandrel 28 , the flat projection 31 extends into the slot 29 . Continued rotation of the mandrel 30 under control of the drive motor 94 , through the shaft 96 , now causes the entire assembly of joined mandrels 30 and 28 to rotate together at the same rate. This occurs immediately after the coil 12 is formed in the tube 10 .
During the time mandrels 28 and 30 are engaged (as indicated in dotted lines in FIG. 6) for rotation together, hot air at a sufficiently high temperature to exceed the thermosetting temperature characteristics of the plastic used in the tube 10 , is applied to the coils 12 through a heater 110 . The coils 12 rotate in the region of the hot air applied from the heater 110 ; and this rotation in thermosetting heat is effected for a length of time sufficient to cause the thermosetting formation of the coil 12 . Once thermosetting of the coil 12 in the tube 10 has been completed, heat application from the heater 110 is discontinued. Continuous rotation of the mandrels 30 and 28 together is effected; and if desired, cooling air may be blown across each of the coils 12 in a conventional manner (not shown) to effect a more rapid cooling down of the parts. Once the parts are sufficiently cooled, the rack 78 / 88 is operated by the control and drive motor mechanism 94 , through the control link indicated in dotted lines 98 , to move back toward the left and to rotate the sleeves 54 and 90 back to the relative positions shown in FIGS. 4, 5 and 7 . The slots 62 and 84 once again are opened. Continued rotation of the mandrels 30 and 28 then causes the assembly, including the sleeves 54 , 90 , 60 and 82 , to rotate where the openings 62 , 83 , 56 and 84 are pointed downwardly; so that gravity allows the finished parts of the type shown in FIG. 2 to drop out of the open slots. Rotation another 180° back to the position shown in FIGS. 4, 5 and 7 is effected. Rotation of the mandrels 30 / 28 ceases; and the mandrel support members 24 and 26 are moved back to the positions shown in FIG. 4 by the control and drive motor mechanism 94 . The finished parts drop free. The system now is ready for a new cycle of operation, repeating all of the steps which have been described above.
The foregoing description of a preferred embodiment of the invention is to be considered as illustrative and not as limiting. Various changes and modifications will occur to those skilled in the art for performing substantially the same function, in substantially the same way, to achieve substantially the same result without departing from the true scope of the invention as defined in the appended claims.
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A machine and method for forming a spring coil in a length of hollow, cylindrical thermoplastic tubing comprises clamping the ends of a predetermined length of cylindrical thermoplastic tubing between first and second opposing spaced clamping members. In the machine, these clamping members include aligned first and second sections of a mandrel. These first and second clamping members then are rotated relative to one another by a predetermined amount selected to be slightly in excess of 360°, while the mandrels are simultaneously moved toward one another, to shorten the distance between the ends of the length of tubing, while the coil is formed. At the end of this relative rotation, the mandrel sections engage one another. The clamped tube, with the coil now formed around the mandrels, is rotated and simultaneously heated to the thermosetting temperature of the tubing. After a sufficient time to establish thermosetting of the coil, the heat is removed. Rotation continues while the tube is cooled. Following the cooling cycle, the apparatus operates to release the tubing with the formed coil in it from the machine.
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This application is a division of allowed application Ser. No. 867,417, filed Jan. 6, 1978, which is a continuation-in-part of application Ser. No. 784,392, filed Apr. 4, 1977, now U.S. Pat. No. 4,149,958 granted Apr. 17, 1979.
FIELD OF THE INVENTION
This invention relates to apparatus and process useful for desalting and/or dehydrating oil-continuous emulsions such as crude petroleum oils, although they can be used in the resolution of other emulsions, which term is herein used as including dispersions. More particularly, the invention relates to such apparatus and process employing multiple electrode/distributor systems located in a single vessel.
BACKGROUND OF THE INVENTION
It is conventional to desalt or dehydrate oil-continuous emulsions by introducing such emulsions directly into an electric treating field of sufficient intensity to coalesce the suspended droplets of the dispersed phase into masses of sufficient size to gravitate from the oil. The dispersed phase of such emulsions is composed of a material, usually aqueous, that is sufficiently immiscible with the oil to produce an internal or dispersed phase. Initially, the dispersed droplets are of such small size or are so stabilized that they will not readily gravitate from the oil phase. However, the electric field coalesces such dispersed droplets, and it is found that the resulting coalesced masses gravitate rapidly from the oil, usually in the same container as that in which electric treatment takes place. In a desalting operation, a quantity of water may be mixed with the incoming crude oil in a valve or other mixer, all as well known, so that a more complete removal of salt from the oil may be accomplished. Typical of such prior art dehydrator/desalters is that described in U.S. Pat. No. 2,880,158 to Delber W. Turner and a version for use on shipboard described in U.S. Pat. No. 3,736,245 to Frederick D. Watson and Howell R. Jarvis. Other related prior art U.S. Pat. Nos. are the following: 2,033,446, 2,527,690, 2,848,412, 3,250,695, 3,592,756, 2,072,888, 2,543,996, 2,892,768, 3,531,393, 2,443,646, 2,557,847, 2,894,895, 3,577,336, and German Pat. No. 1,014,076 (Helmut Stock; Aug. 22, 1957).
It is an object of this invention to provide a dehydrating/desalting apparatus, especially useful for desalting crude oil, that employs multiple electrode/distributor systems located in a single vessel to achieve serial stage desalting and/or vastly increased oil handling capacity in a parallel stage operation.
It is a further object of this invention to provide a process for desalting curde oil in a plurality of serial stages.
Further objects of the invention will be evident to those skilled in the art in the course of the following description.
SUMMARY OF THE INVENTION
In accordance with this invention, there is provided an electric treater for resolving oil-continuous emulsions and other emulsions and for desalting of liquids such as crude oil, such treater comprising a closed vessel provided with a plurality of coalescing stages with no impermeable barriers between them. The stages are isolated hydraulically, i.e., are hydraulically substantially independent, to allow parallel or serial stage operation, each stage being provided with permeable, planar electrode means which provide an electric field to cause coalescing of the dispersed phase, ordinarily water or brine, the electric fields being superimposed.
The system is composed of multiple electrode assemblies, each with individual distributor systems with the hydraulics controlled to isolate the individual stages to allow multiple stage operation. The system can also be used to process oils by utilizing the separate electrode/distributor assemblies for parallel flow of material through the system. The use of two or three stages is preferred, although a greater number may be employed.
When employed for serial stage desalting, collector pumps are arranged between successive coalescing stages and conduits provided so that the treated liquid from one stage is returned as the feed for the succeeding stage. The electrodes are preferably horizontally disposed planar electrodes in vertically spaced relationship. The treatment vessel may be in the form of a sphere, a horizontally elongated cylinder substantially longer in length than in width, or of other suitable form.
When employed for parallel stage desalting, a common conduit means is employed for supplying oil-water emulsion to each of the distributor systems.
DETAILED DESCRIPTION OF THE INVENTION
The invention is illustrated by but not limited to the following exemplary embodiments.
Referring to the drawings:
FIG. 1 is a transverse vertical cross section of one embodiment of an electrical treater of the present invention intended for serial stage operation.
FIG. 2 is a longitudinal vertical cross section taken along line 2--2 of the electrical treater shown in FIG. 1.
FIG. 3 is a transverse vertical cross section of another electrical treater of this invention intended for serial stage operation.
FIG. 4 is a vertical cross section of yet another electrical treater of this invention intended for serial stage operation.
FIG. 5 is a vertical cross section of an electrical treater of this invention intended for parallel stage operation.
FIG. 6 is a schematic illustration of a vertical cross section of a three stage series electrical treater of this invention.
FIG. 7 is a transverse vertical cross section of another embodiment of the electrical treater of present invention intended for parallel stage operation.
FIG. 8 is a longitudinal vertical cross section of the electric treater shown in FIG. 7.
FIGS. 1 and 2 illustrate one embodiment of the invention, especially useful when it is desired to convert an existing Petreco high velocity desalter to two stage series operation. The desalter consists of a horizontally disposed generally cylindrical vessel 1 having rounded ends 2, which may suitably have a diameter of about 8 to 14 feet. Lengths of about 25 feet and 49 feet and as much as 133 feet have proved suitable with a 12 foot diameter vessel. Inside the vessel 1 are three horizontally disposed planar electrodes 3, 4 and 5. Upper electrode 3 and bottom electrode 5 extend almost the entire length and width of the vessel 1, electrode 5 being downwardly curved in the vicinity of its longitudinal axis to accommodate distributor 6. These electrodes are energized. Middle electrode 4, which is at ground potential, is in contact with the wall of vessel 1. The electrodes 3, 4 and 5 are spaced about 6 to 15 inches apart, 10 inches being very suitable. Each electrode may be permeable, e.g., be a grid of metal rods or pipes, suitably of cold finished steel, of a structure similar to that shown in U.S. Pat. No. 2,880,158.
A distributor 6, serving as the first stage distributor, and shown here as a box-like conduit or header, extends horizontally for most of the length of vessel 1 just under middle electrode 4, to which it may be attached, and along its longitudinal axis. Bottom electrode 5 may be downwardly curved as shown in the vicinity of its longitudinal axis to accommodate distributor 6. Orifices 7 are provided in the sides of the conduit all along its length. However, instead of a box-like conduit, a pipe with holes drilled in it may be substituted. Distributor 6 is supplied by mixing valve 8 via conduit or riser pipe 9. Mixing valve 8 is supplied by oil conduit 10 and water conduit 11, which may be connected with pump 12 and recycle conduit 13, as shown, and/or a fresh water source not shown. Interstage outlet collectors 14, which may be drilled pipes supported at the vessel wall with angle clips (not shown) extend longitudinally along the sides of tank 1, and are connected to conduit 15 which leads to oil recycle pump 16 and thence to conduit 17. Conduit 18, connected to a fresh water source, leads into conduit 17, which leads to mixing valve 19. A conduit 20 extends from mixing valve 19 to distributor modules 21, which may be similar in structure to that shown in Turner U.S. Pat. Nos. 2,543,996, 2,527,690. Although three such modules are shown here, a lesser or greater number may be employed. For example, in a 49 foot long vessel, four such modules may be used. An outlet collector 22, which may be a pipe with holes drilled in the upper wall, extends horizontally along the top of tank 1 and leads to outlet 23 and conduit 24. A water effluent conduit 25 is connected to the lower part of vessel 1.
In operation, the temperature of the crude oil depends upon the crude specific gravity and the type of crude. However, in many cases of crude oil, temperatures of between about 100° F. and 350° F., with about 250° F. being optimum, are used. The pressure must be sufficient to keep the oil and water mixture liquid at the operating temperature. The crude oil is charged by conduit 10 and water is added via conduit 11, which is supplied by recycle conduit 13. The oil may be brought to the desired temperature by any suitable procedure, such as by heat exchange with another refinery stream. The amount of water added is suitably about 10% of the crude oil charged. The two fluids are mixed in mixing valve 8 to form an emulsion. The emulsion is carried through riser pipe 9 to the first stage distributor 6, from whence it flows between middle electrode 4 and bottom electrode 5 in either direction in a generally horizontal transverse direction toward the sides of the vessel 1 where the interstage collectors 14 are located. Water which has been thrown out of emulsion by the electric field between electrodes 4 and 5 falls toward the bottom of vessel 1, where a pool of collected water is maintained. The main portion of the treated oil is taken up by collectors 14 and is pumped by interstage pump 16 to conduit 17. A 5% addition of fresh water takes place in this conduit and is emulsified into the oil by mixing valve 19. The second stage emulsion thus formed is carried by conduit 20 to second stage distributors 21 from whence it flows between electrodes 3 and 4 in either direction, more or less transversely, to the sides of the vessel 1. The treated oil passes upwardly near the edge of electrode 3 and along the sides of the vessel 1 and leaves the vessel by means of outlet collector 22, outlet 23 and conduit 24. The arrows shown in the figures indicate the path of the fluids through the conduits and, in a general way, inside the vessel 1.
The level of the interface 26 of the water with the treated oil may be maintained automatically at the desired position in the lower portion of vessel 1. As shown in the drawings, this is accomplished by means of motor valve 27 on effluent conduit 25, which valve is actuated between open and closed positions by a float 28 connected to a control unit 29, which delivers an acutating signal through an interconnection, indicated by dashed line 30, to valve 27. The float 28 senses the water level interface 26, and the valve 27 is controlled to maintain the interface 26 at the desired level in the lower portion of vessel 1. Other liquid level control means for maintaining the interface 26 at the desired level, such as an electrical capacitance probe, may be employed.
While the above described embodiment is of special interest in the conversion of existing desalting units having distributors 21 already present, desalters are also contemplated and within the scope of this invention wherein both the first and second stage distributors may take the form of the boxlike conduit 6 or drilled pipe. Similarly, both first and second stage distributors may take the form of distributors 21. Moreover, either or both stage distributors may be supported by and supplied either from the top or bottom of vessel 1, or otherwise.
In the embodiment described above, the top and bottom electrodes 3 and 5 are each energized with its own transformers, here not shown, and the middle electrode 4 is at ground potential. However, it is also contemplated and within the scope of this invention that the top and middle electrode be charged individually and the bottom electrode grounded. A potential difference of about 15,000 to 33,000 volts may suitably be maintained between electrodes 3 and 4 and between electrodes 4 and 5. The energized electrodes may be opposed electrodes if single phase current is employed or two legs of a three phase current (3 phase open Δ) where the grounded electrode is the middle one. Moreover, if a three phase system is used, all three electrodes may be energized. The supports and curcuitry for the electrodes are omitted in FIGS. 1 and 2 but may be the same as that shown in FIG. 3, described below.
FIG. 3 is a representation of a vertical cross-section of an embodiment of the invention using a horizontal cylindrical vessel 1 with boxlike conduits 6 and 6a as distributors in both stages and otherwise similar in its main features and operation to that shown in FIGS. 1 and 2. The reference numerals in this figure correspond to those employed in FIGS. 1 and 2 for the same or similar features.
In this embodiment distributors 6 and 6a are both fed from below by riser pipes 9 and 20, respectively. The water leaves vessel 1 by means of a single conduit 13 which supplies recycle water to conduit 11 and effluent to conduit 25a. Motor valve 27 on conduit 25a is actuated by a signal from control unit 29. Upper electrode 3a in this embodiment is upwardly curved in the vicinity of its longitudinal axis to accommodate distributor 6a, being symmetrical in this respect to bottom electrode 5.
Electrode 3a is suspended by one or more vertical insulators 31 and rods 32, as required to support the weight of the electrode. Similarly electrode 5 is suspended by one or more vertical insulators 33 and rods 34. Electrodes 3 and 5 are energized by transformers 35 and 36, respectively. The middle electrode 4 is at ground potential. It is suitably fastened to the vessel 1, for example, by means of attached rail bars 43, vessel 1 being grounded. As shown here, transformers 35 and 36 are step up transformers having reactors 37 and 38 in series with the respective primaries. The secondaries have one end grounded and energize conductors 39 and 40, respectively, which connect through entrance bushings 41 and 42, respectively, to electrodes 3a and 5.
FIG. 4 is a representation of a vertical cross section of a spherical desalter such as the Petreco spherical desalter which has been converted to two stage series operation. The reference numerals in this figure also correspond to those employed in FIGS. 1 and 2 for the same or similar features. Vessel 1b is a spherical container which may have a diameter of up to 42 feet, suitably 18 feet. In this embodiment, both first and second stage distributors 6b and 21b are brought in and supplied from the bottom of the vessel. The first stage distributor 6b is, as shown here, a circular box supplied by conduit 9b and built around riser pipe 20b and having orifices 7b around its periphery to control flow distribution. Electrodes 3b, 4b and 5b are circular, as required to fit the cross section of the spherical vessel 1b, electrode 4b being suitably fastened to the vessel 1b, for example, by means of attached rail bars 43b, vessel 1b being grounded. Collectors 14b, which may be drilled pipes arcuately shaped to conform to the sides of vessel 1b, and supported at the vessel wall with angle clips (not shown), are positioned to take up the main portion of the oil treated in the first stage. The treated oil is carried by conduit 15b to recycle pump 16. The operation of this desalter is otherwise similar to the embodiments described above.
In each of the above described embodiments, the exit velocity from the drilled pipe distributor or the orifices of the distributor 6 or 6b is such that there is enough inertial energy to carry the emulsion in a horizontal plane between the treating electrodes 4 and 5 or 4b and 5b to the interstage collectors 14 or 14b. These collectors are located to collect the first stage treated oil and some "override" of fluid from the second stage of treatment. The interstage pumping rate is controlled so that it exceeds the rate at which the treated oil is withdrawn from the unit by the second stage outlet collector. This may be accomplished by operating the recycle pump 16 at a pumping rate 10 to 20% faster than the initial charging rate.
FIG. 5 is a representation of a vertical cross section of a desalter having two parallel stages. Such a system has the potential of doubling the oil handling capacity of a typical single electrode, single distributor system. The reference numerals in this figure correspond to those employed in FIGS. 1 and 2 for the same or similar features. In this embodiment, riser pipe 9c supplies both distributors 6c and 6d, shown here as the boxlike conduit type. In operation, about 5% of water by volume based on the oil feed is introduced by conduit 18c and pump 16c and is mixed in mixing valve 19c with crude oil introduced in conduit 10c. The mixture then passes into conduit 9c. The oil-water mixture is distributed in two parallel paths, one between electrodes 3c and 4c and the other between electrodes 4c and 5c, electrodes 3c and 5c being energized and 4c being at ground potential. The oil-water mixture travels toward the sides of vessel 1 in each instance and thence upward toward outlet collector 22c where the treated oil is withdrawn. The salt containing water is separated from the oil-water mixture by the passage between the electrodes and drops downwards into the pool of water at the bottom of the vessel 1c, the level of which, represented by interface 26, is maintained by effluent conduit 25, float 28, control unit 29, interconnection 30 and motor valve 27, as described in connection with FIGS. 1 and 2.
Three or more separate electrode-distributor systems can also be used if higher oil handling capacities are desired.
FIG. 6 is a schematic representation of a vertical cross section of a desalter employing three desalting stages in series. The reference numerals correspond to those employed in FIGS. 1 and 2 for the same or similar features. In this embodiment, a fourth planar, horizontally disposed electrode 44 is employed in addition to the three electrodes 3d, 4d and 5d, similar to those shown in the previously described embodiments. Electrode 44 is positioned below electrode 5d. Electrodes 3d, 5d and 44 are energized and electrode 4d is at ground potential. An additional distributor 6g, positioned between electrodes 5d and 44, is employed in addition to distributors 6e and 6f and a second interstage collector 14e is employed in addition to first interstage collector 14e. The distributors are all shown as boxlike conduits. In this embodiment, distributor 6g serves as the first stage distributor; distributor 6f as a second stage distributor; and distributor 6e serves as a third stage distributor. Fresh water for desalting is supplied to each desalting stage, although recycle water may be employed in the first stage. The treated product leaves the vessel 1 through outlet collectors 22d and water is removed through outlet 25d. The various conduits, valves and pumps removing and supplying fluids to and from the various stages and the electrical circuitry are not shown, but their nature will be evident from the descriptions of the embodiments shown in FIGS. 1 to 4.
In an analogous manner to that of FIG. 6, desalters with more than three stages may be constructed.
FIGS. 7 and 8 are representations of transverse and longitudinal cross sections, respectively, of the internal details of a desalter having two parallel stages, such as shown in FIG. 5. The embodiment shown is especially useful in the conversion of an existing Petreco low velocity desalter to parallel stage operation. The reference numerals in these figures correspond to those employed in FIGS. 1, 2, 3 and 5 for the same or similar features. As shown in FIGS. 7 and 8, the desalter comprises a horizontal cylindrical vessel 1e with hemispheric heads 2e. Upper and lower portions, 6c and 6d, respectively, of a box-like conduit type distributor extend horizontally for most of the length of vessel 1e and are equipped with rows of orifices 7c and 7d along its length on both sides. The distributor is supplied with oil-water emulsion produced by a mixing valve, not shown, by riser pipe 9d and riser pipe extension 9e. Grounded electrode 4e is supported at the sides of vessel 1e and the distributor by rail bars 43 and 44, respectively. Charged electrodes 3e and 5e are supported by vertical insulators 31e and 33e, respectively, and rods 32e and 34e, respectively, said insulators being supported from the upper part of the wall of vessel 1e, as by hooks 45 and 46, and stabilized structurally by tie-rods 50, which also serve as electrical conductors. Power is transmitted to the charged electrodes 3e and 5e by a wire conductor 47 passing through entrance bushing stub 48, spring contactor 49, tie-rods 50 and from thence by rods 34e to electrode 5e and by monel tiller rope 51 and rods 32e to electrode 3e. Outlet collector 22e, supplied with vortex spoilers 52 at its intakes, leads to product effluent conduit 24e. The level of the interface 26 between the water and the oil is maintained by a level control, not shown, which is actuated by displacer hanger rod 53, connected to displacer 54, a weighted, tubular sealed float, which moves up and down with the level change. (The water layer is not shown in section so as not to obscure details of the drawing.) Displacer 54 is guided by displacer shield 55 which is supported by supports 56. Displacer 54 is designed to exert a predetermined tension on rod 53 under the operating pressure and temperature, with the bottom half of the displacer in the water layer and the top half in the oil layer. Since there is not a sharp demarcation between the two layers, displacer 54 is made long to allow for an emulsion of oil and water to exist at the oil-water interface. The predetermined tension on rod 53 is transmitted to a level control sensor instrument, not shown, which converts the tension stress into torsion which twists a torque tube. This in turn causes movement of a Bourdon tube which affects the air being delivered to actuate a water bleed valve, not shown, on an effluent conduit, also not shown, connected to outlet 25. A rise in the water level lessens the tension on rod 53 and a fall in the water level increases it, causing the water bleed valve to open or close and thus readjust the water level to balance the forces in the control system. Water effluent outlet 25 is located in the lower portion of vessel 1e. A low level float 57 operates to maintain safety when vessel 1e is not liquid full. If the liquid level falls to a predetermined position, electrically conductive arm 59 attached to float lever 58, also electrically conductive, makes contact with conductor 60, attached to tie-rod 50. Float lever 58 is connected to pivot point 61 on support 62, which is connected structurally to vessel 1e. When arm 59 contacts conductor 60, conductor 60 is thus electrically connected with the grounded vessel 1e. Any vapor accumulation in vessel 1e concomitant with the drop in liquid level thus causes float 57 to drop and a short circuit to occur. With the short circuit and resultant reactance, the voltage to the transformer is so reduced that no high voltage is admitted to electrodes 3e and 5e via conductor 47. Therefore, the possibility of a spark and resulting explosion if air were also present in the vapor is avoided. The mode of operation of this embodiment is otherwise as described in connection with FIG. 5, the path of the oil being shown by the arrows.
A horizontal parallel stage desalter as above described, measuring 8 feet in internal diameter and 6 feet horizontally, tangent to tangent, was used to treat 48° API waxy Michigan crude oil. The oil was treated at 260° F. with 1 pint of liquid demulsifier consisting of a mixture of an oxyalkylated phenol-formaldehyde resin, an ammonium salt of an alkaryl sulfonate and an acylated polyalkanolamine, all in solvent, added per 1000 barrels of curde oil (said demulsifier being a Tretolite® demulsifier of the Tretolite® DS series of demulsifiers), the pressure differential across the mixing valve being 10 p.s.i.g., the voltage being 440 volts and the load 10 amperes. A charge rate of 6500 barrels per day was employed, the crude being desalted from 80 pounds to 1 pound per thousand barrels of oil. Bottom sediment and water (BS&W) in and out was 0.2%. In another run, at a temperature of 253° F., the desalted oil contained 18 pounds per thousand barrels with 400 volts and a 23 ampere load. Other Tretolite® demulsifiers of the Tretolite® DS series or any functionally equivalent desalting liquid demulsifier may also be used.
Other electrode arrangements than those described in the above embodiment may be employed in parallel stage desalting, for example, arrangements corresponding to those described in connection with FIGS. 1 and 2, above. Similarly the oil temperature and pressure parameters and potential difference between electrodes described in connection with FIGS. 1 and 2 apply also to parallel stage desalting.
The various distributors, collectors and electrodes described above may be supported in part by conventional means well known in the art, such as guy wires, in addition to being supported by the conduits and other support means disclosed.
It will be apparent from the foregoing description that the invention is not limited to a particular shape of vessel, electrical circuitry, voltage employed, type of distributors, water level control means, arrangement of conduits, etc. Many embodiments, modifications, developments, and variations of forms are contemplated as long as they fall within the broad scope of the appended claims.
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A desalter/dehydrator having a plurality of electrified coalescing stages in a single vessel, wherein the stages are isolated hydraulically to allow parallel or serial stage operations. In one embodiment, several electrical stages, each separately energized, are operated in parallel to proportionately increase vessel throughput capacity. In another embodiment, series operation is employed, wherein each successive stage receives the product from the preceding stage as feed, with fresh water being added. Placement of electrodes, distributors, collectors, etc. are determined by the type of operation to be performed in the vessel.
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SUMMARY OF THE INVENTION
The invention of this application relates to a liquid filter which includes means carried by the cover for the filter housing by which the filter elements are retained within the housing.
Multiple element filters of this nature are shown in U.S. Pat. No. 4,022,693. The cover of such a filter is used to overlie and retain the filter elements which are supported by the filter housing. While this is an effective way to retain the filter elements, the location and number of elements is somewhat limited.
The filter of this invention includes a housing having an upper wall with a plurality of openings therein for supporting filtering elements. The filter also includes a cover which seals against the housing in its closed position. The cover has a dome-shaped inner face and carries a grid at its lower peripheral edge. The grid is open and presses against the filter elements at their upper ends to retain them in position when the cover is closed. The liquid entering the filter flows from an inlet passageway into the domed area under the cover, through the grid openings, and through the filtering elements into the housing body for removal via an outlet passageway. The grid provides the capability of retaining various patterns of filter element arrangements in the housing top wall without regard to number or precise location of the elements.
Accordingly, it is an object of this invention to provide an improved multiple element liquid filter.
Another object of this invention is to provide a liquid filter having a grid carried by the cover of the filter for retaining filter elements in place when the cover is closed.
Still another object of this invention is to provide a liquid filter having a capacity to retain various arrangements of filter elements in the filter housing.
Other objects of this invention will become apparent upon a reading of the invention's description.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of the filter of this invention with the cover closed.
FIG. 2 is a perspective view of the filter with the cover removed.
FIG. 3 is a top plan view of the filter with the cover removed.
FIG. 4 is a sectional view of the filter taken along line 4--4 of FIG. 3 but with the cover closed.
FIG. 5 is a perspective view of the filter with portions cut away for purposes of illustration.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The preferred embodiment illustrated is not intended to be exhaustive nor to limit the invention to the precise form disclosed. It is chosen and described in order to explain the principles of the invention and its application and practical use to thereby enable others skilled in the art to best utilize the invention.
The multiple element filter 10 of this application is a filter for liquids. Filter 10 includes a body which is generally cylindrically shaped and which includes a side wall 12, a lower wall 14 and an upper wall 16. A cover 18 is adapted to overlie upper wall 16. The body of filter 10 is supported by legs 20 attached to side wall 12. Upper wall 16 has a central opening 22 which serves as an inlet passageway for liquids entering the filter through an inlet pipe 24. Pipe 24 enters filter 10 in a sealed manner through lower wall 14 and extends vertically into opening 22 in upper wall 16. A second pipe 26 serves as an outlet passage for liquids and communicates with the interior of filter 10 through side wall 12 at lower wall 14. Upper wall 16 has a series of openings 28 formed in it which are located circumferentially about inlet opening 22. A filter element 30 extends through each opening 28 and is supported by upper wall 16 at a peripheral shoulder 32. Each filter element is bag-shaped and has an open top end formed by a ring part 34. Filter elements 30 may be formed of a screen or similar generally rigid reticulated material, cloth or a similar flexible interwoven filtering material, or a combination of both a reticulated screen which serves as a shape retaining member and an interfitting interwoven filtering material. Each filter element 30 extends downwardly through its accommodating opening 28 with its ring part 34 being seated upon an upper wall shoulder 32 about the opening.
Cover 18 spans upper wall 16 and has a dome-shaped inner cavity 36 which is located spacedly above the upper surface of upper wall 16. Cavity 36 is defined in part by a cover side wall 37. Side wall 37 is circular to accommodate cylindrical body side wall 12. Cover side wall 37 carries a grid 38. Grid 38 is attached at its circumference to cover side wall 37 and spans cavity 36. Grid 38 is formed by spaced parallel crossbars 40 which run lengthwise across the circumference of cavity 36 and spaced parallel crossbars 42 which overlie crossbars 40 and run lengthwise across the circumference of cavity 36 transverse to crossbars 40. Crossbars 40 and 42 form an open grid pattern. Grid 38 overlies ring parts 34 of filter elements 30 to hold the filter elements within openings 28 in body upper wall 16 when the cover is in its closed position, as best seen in FIG. 4.
Cover 18 is secured to body wall 12 by means of eyebolts 44 mounted to body side wall 12 and hold-down nuts 52 as shown. Leakage between cover 18 and the filter body is prevented by a continuous sealing member 54 located at the periphery of upper wall 16. Sealing member 54 may be formed of rubber or flexible plastic material and is seated in a circular groove 56 formed in upper wall 16.
In operation, as shown by arrows 60, liquid enters filter 10 by pipe 24 and flows upwardly in the pipe where it is discharged through opening 22 above upper wall 16 within cavity 36. The liquid then flows downwardly through grid 38 and filtering elements 30, into the interior of filter 10, and out through pipe 26. When it is desired to clean or replace one of filtering elements 30, nuts 52 are loosened, eyebolts 44 are pivoted out of engagement with cover 18 and the cover lifted from upper wall 16 of filter 10. Each filtering element can then be removed from each opening 28 and either cleaned, repaired or replaced in preparation for the next filtering operation.
It is to be understood that the invention is not to be limited to the details above given but may be modified within the scope of the appended claims.
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In a filter for liquids including a housing which suspends multiple filtering elements and a cover. A grid is carried by the lower peripheral edge of the cover which overlies and holds the filtering elements in place when the cover is in sealing contact with the filter housing.
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This application claims priority to U.S. Provisional Application No. 60/256,483, filed Dec. 20, 2000.
FIELD OF INVENTION
The present invention relates to an inclusion complex formed between cyclodextrin and drospirenone, to methods of providing such an inclusion complex, and to a method of increasing the water solubility of drospirenone by providing such an inclusion complex. Moreover, the present invention relates to the use of said inclusion complex in pharmaceutical compositions for use as a medicament in the treatment of symptoms associated with menopause and in female contraception.
BACKGROUND OF THE INVENTION
Drospirenone (6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone), which may be prepared substantially as described in e.g. U.S. Pat. No. 4,129,564 or WO 98/06738, is only sparingly soluble in aqueous media at various pH values.
The water solubility of a compound is extremely pertinent with regards to its utility in industry, particularly in the pharmaceutical industry where there is a strong link between water solubility and bioavailability. The therapeutic efficiency of drospirenone may be improved by increasing its overall water solubility, thus providing for routes of administration alternative to those proceeding via the gastrointestinal tract, where absorption is slow and then rapidly cleared from circulating blood by the liver.
Cyclodextrins are known to solubilize nonpolar compounds and improve the absorption of certain compounds by forming complexes with said compounds. The cyclodextrins are frequently derivatized in order to improve the solubility or to accommodate appropriately the compound of interest. However, certain compounds are not well accommodated by the cavity of the some of the cyclodextrin molecules.
Drospirenone, in its uncomplexed form, is known from DE 26 52 761 in which its use as a diuretic compound is disclosed.
U.S. Pat. No. 4,596,795 discloses a complex between α-, β- and γ-cyclodextrins and derivatives thereof with testosterone, progesterone, and estradiol and the solubility of said complexes.
U.S. Pat. No. 5,885,978 relates to a composition comprising an adrenal cortical steroid and cyclodextrin prepared by clathrating the adrenal cortical steroid in the cyclodextrin using a homomixer.
U.S. Pat. No. 5,376,641 discloses a method of making a steroid water soluble by mixing a steroid and a branched beta cyclodextrin together in water for a period of 4 to 24 hours under ambient conditions.
U.S. Pat. No. 5,376,641 discloses a method for making a steroid water soluble by complexing the steroid with branched β-cyclodextrin.
U.S. Pat. No. 4,727,064 discloses a method of improving the dissolution properties of a steroid by forming a solid comprising at least one of testosterone, progesterone and estradiol as an inclusion complex with a poly-β-cyclodextrin and /or hydroxypropyl-β-cyclodextrin adapted for administration by buccal route.
FR 2 515 187 discloses inclusion complexes between γ-cyclodextrines and various steroids, such as a spironolactone steroid.
WO 96/02277 discloses pharmaceutical compositions containing cyclodextrin-clathrate complexes of steroid sexual hormones for protection against oxidative degradation of steroids.
SUMMARY OF THE INVENTION
The invention relates to an inclusion complex between cyclodextrin and 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone).
The invention also relates to methods for producing an inclusion complex between cyclodextrin and drospirenone comprising combining drospirenone and cyclodextrin at a molar ratio of from 0.3:1 to 20:1, preferably 1:1, 2:1, 3:1, 4:1 or 5:1, most preferably 2:1 or 3:1, particularly 3:1.
One object of the present invention is to increase the water-solubility of drospirenone. The present invention thus further relates to methods for improving the solubility of drospirenone, said method comprising forming an inclusion complex between drospirenone and cyclodextrin.
In a further aspect of the invention, pharmaceutical compositions comprising an inclusion complex of drospirenone and cyclodextrin are anticipated. Consequently, the use of the inclusion complex between drospirenone and cyclodextrin as a medicament and for the preparation of a composition for female contraception or for the treatment of menopausal symptoms are defined herein. Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
DETAILED DESCRIPTION OF THE INVENTION
The term “inclusion complex” is intended to mean a complex wherein at least a moiety of drospirenone has inserted itself, at least partially, into the cavity of cyclodextrin.
In efforts to improve the functional utility of drospirenone, research has led to a new chemical entity, an inclusion complex between cyclodextrin and drospirenone. The cyclodextrin, may be selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or derivatives thereof. Preferred embodiments of the present invention are that of a complex between drospirenone and β-cyclodextrin or derivatives thereof or a complex between drospirenone and γ-cyclodextrin or derivatives thereof, most preferably a complex between drospirenone and β-cyclodextrin or γ-cyclodextrin, particularly β-cyclodextrin.
The cyclodextrin, as stated, may be selected from the group comprised of α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin, i.e. the 6-, 7-, or 8-sugar unit macrocycle, respectively. The cyclodextrin may be modified such that some or all of the primary or secondary hydroxyls of the macrocyle, or both, may be alkylated or acylated. Methods of modifying these alcohols are well known to the person skilled in the art and many derivatives are commercially available. The cyclodextrin may be modified such that one or more of the primary or secondary hydroxyls of the macrocyle, or both, may be alkylated or acylated. Methods of modifying these alcohols are well known to the person skilled in the art and many are commercially available. Thus, some or all of the hydroxyls of cyclodextrin may be substituted with an O—R group or an O—C(O)—R, wherein R is an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 2-6 alkynyl, an optionally substituted aryl or heteroaryl group. R may be methyl, ethyl, propyl, butyl, pentyl, or hexyl group. Consequently, O—C(O)—R may be an acetate. Furthermore, R may be such as to derivatize cyclodextrin with the commonly employed 2-hydroxyethyl group, or 2-hydroxypropyl group. Moreover, the cyclodextrin alcohols may be per-benzylated, per-benzoylated, or benzylated or benzoylated on just one face of the macrocycle, or wherein only 1, 2, 3, 4, 5, or 6 hydroxyls are benzylated or benzoylated. The hydroxyl groups of cyclodextrin may be per-alkylated or per-acylated such as per-methylated or per-acetylated, or alkylated or acylated, such as methylated or acetylated, on just one face of the macrocycle, or wherein only 1, 2, 3, 4, 5, or 6 hydroxyls are alkylated or acylated, such as methylated or acetylated.
In a preferred embodiment of the invention, the inclusion complex is between β-cyclodextrin or γ-cyclodextrin and drospirenone. Most preferably, the inclusion complex is between β-cyclodextrin and drospirenone and in a further interesting embodiment thereof, the β-cyclodextrin is unmodified.
One or more drospirenone molecules may be included into the cavity of the cyclodextrin molecule. Conversely, one molecule of drospirenone may be included into the cavity of one or more cyclodextrin molecules. The inclusion complex may exist in a variety of molar ratios. The molar ratio between drospirenone and the cyclodextrin is dependent on a variety of physical factors during the formation of the inclusion complex. Furthermore, the molar ratio of the inclusion complex may be transitional and vary during its preparation. Given the inclusion of drospirenone can result from a variety of interactions with any number of functional groups or moieties of drospirenone, the depth at which drospirenone is included within the cavity of a cyclodextrin may vary. Furthermore, the size of the cavity, which depends on the selection of cyclodextrin (α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin) and on whether the numerous free hydroxyl groups present on the periphery of the cavity of a cyclodextrin molecule are partially or fully derivatized, will influence the ability for drospirenone to include itself into the cavity. These factors, amongst others, influence the molar ratio of the inclusion complex.
Without being limited to a particular manner in which the inclusion complex is formed, it is presumed that the inclusion complex is an inclusion complex wherein hydrophobic interactions favour the inclusion of hydrophobic moieties from drospirenone into the cavity of a cyclodextrin molecule, given the relative hydrophobicity of the numerous alkyl groups in the cavity of the cyclodextrin.
Given the above-stated factors, and that the moiety of the drospirenone molecule which may include itself into the cyclodextrin molecule may vary, the molar ratio between drospirenone and the cyclodextrin, respectively, may be 1:1, 2:1, 3:1, 3:2, 1:2, 2:2, 2:3 or 1:3. Preferably a 1:1 or 1:2 molar ratio exists between drospirenone and cyclodextrin; namely, one molecule of drospirenone, or a moiety thereof, is at least partially inserted into the cavity of one cyclodextrin molecule or one molecule of drospirenone, or moieties thereof, is at least partially inserted into the cavity of two molecules of cyclodextrin. Alternatively, a 2:1 molar ratio may exist between drospirenone and cyclodextrin; namely, two molecules of drospirenone, or moieties thereof, are at least partially inserted into the cavity of one cyclodextrin molecule.
The term “solubility” in connection with drospirenone is intended to mean the solubility of the inclusion complex between drospirenone and cyclodextrin in water. The term “total solubility” relates to the drospirenone concentration in a phase solubility isotherm, namely to the solubility of uncomplexed and complexed drospirenone. The “total solubility” is a function of the cyclodextrin concentration.
Given one of the objects of the present invention is to increase the solubility and total solubility of drospirenone, it is preferred that the inclusion complex is such that the total water solubility of drospirenone at 20° C. is increased by a factor of at least 2, such as at least 2.5, at least 3, at least 3.5, or at least 4 compared to drospirenone in an uncomplexed form.
Correspondingly, it is preferred that the total solubility of drospirenone in water at 20° C. is increased to at least 9×10 −5 mol/L, such as at least 1×10 −4 mol/L, 2×10 −4 mol/L, 3×10 −4 mol/L or 3.5×10 −4 mol/L.
The inclusion complex may exist in the form of a hydrate containing varying amounts of water, such as between about 1% and 25% water. The degree of hydration may vary according to, amongst other reasons, the degree of substitution of the hydroxyls, the method of preparation and the molar ratio of the inclusion complex. The water content of the inclusion complex may depend on the manner in which the inclusion complex is stored, the temperature, pressure and relative humidity. Thus, any discussion on the solid state form of the drospirenone-cyclodextrin inclusion complex comprises the range of hydrates. The hydrate water is part of the crystal lattice and thus modifying the water content may change the crystal lattice and possibly some of the physical properties of the inclusion complex.
As is known to the person skilled in the art, cyclodextrin itself forms an inclusion complex with water. Thus, the cyclodextrin used in the preparation of the drospirenone-cyclodextrin inclusion complex may be in a hydrated form or in an anhydrous form.
A further object of the invention is to provide a method for producing an inclusion complex comprising the step of combining cyclodextrin and drospirenone at a molar ratio of from 0.3:1 to 20:1, preferably 1:1, 2:1, 3:1, 4:1 or 5:1, most preferably 2:1 or 3:1, particularly 3:1.
The term “solution” in connection with cyclodextrin or drospirenone and in connection with the preparation of an inclusion complex is intended to comprise embodiments wherein the solute, namely cyclodextrin or drospirenone, is fully or partially dissolved in the solvent so as to form a homogenous solution, a saturated solution, a super-saturated solution, a slurry or a suspension.
In the preparation of the inclusion complex according to the present invention, the combining of the components may be done using a solution of cyclodextrin, comprising organic solvent or an aqueous solution such as water. In some embodiments of the invention, the solvent comprises a mixture of water and an organic solvent. The organic solvent may be selected from any of those commonly used in organic synthesis such as, but not limited to, THF, methylene chloride, diethyl ether, petroleum ether, ethyl acetate, dioxane, DMF, DMSO, acetone, acetonitrile, ethanol, methanol, pyridine, or combinations thereof. Preferably, the organic solvent is miscible with water. Polar solvents are preferred such as water, methanol, ethanol, DMSO, DMF, and pyridine, most preferably water or ethanol, particularly water.
A solution of cyclodextrin, as described supra, in any concentration or degree of homogeneity, may be combined with solid drospirenone. Alternatively, the cyclodextrin solution may be combined with a solution of drospirenone. In the embodiment where a solution of cyclodextrin is combined with solid drospirenone, drospirenone may be in its micronized form.
In the embodiment where a solution of cyclodextrin is combined with a solution of drospirenone, drospirenone may be fully or partly dissolved in an organic solvent or water. Organic solvents may be selected from any of those known to the person skilled in the art such as, but not limited to, THF; methylene chloride, diethyl ether, petroleum ether, ethyl acetate, dioxane, DMF, DMSO, acetone, acetonitrile, ethanol, methanol, pyridine, or combinations thereof.
It follows that a solution of drospirenone, as described supra, in any degree of homogeneity and in any concentration may be combined with solid cyclodextrin in the preparation of an inclusion complex between cyclodextrin and drospirenone.
Alternatively, solid drospirenone and solid cyclodextrin may be combined in their solid forms and then combined with water or an organic solvent.
In a preferred embodiment of the invention, a method of producing an inclusion complex comprises the steps of dissolving cyclodextrin in water, optionally with the aid of heating, to form a cyclodextrin solution; dissolving drospirenone in a solvent selected from the group comprising of water and ethanol or mixtures thereof, optionally with the aid of heating, to form a drospirenone solution; combining the cyclodextrin solution and the drospirenone solution to form a combined solution; stirring the combined solution, preferably while keeping the solution at or below 25° C.; filtering the resultant precipitate; washing the precipitate with a solvent selected from the group consisting of water, ethanol, ether and acetone, preferably wherein the solvent is cooled to below 25° C.; optionally suspending the resultant solid in a solvent, preferably acetone, and washing the suspended material with a solvent selected from the group consisting of water, ethanol, ether and acetone, preferably wherein the solvent is cooled to below 25° C.; removing substantially all of the solvent from the solid material. Preferably, the solvent is removed by spray drying or alternatively by lyophilization.
The method of preparation may further comprise mechanical mixing, agitation or shaking, or heating of the solutions or combined components.
In embodiments of the invention wherein an organic solvent is used in the combination of drospirenone or cyclodextrin, the inclusion complex formed may contain one or more molecules of said solvents, depending on the method of drying, precipitation or crystallisation. The complex may alternatively exist in the form of a hydrate containing varying amounts of water.
A typical preparation of the drospirenone-cyclodextrin inclusion complex may be as follows: Drospirenone is dissolved in a solvent such as acetone or ethanol. The cyclodextrin is dissolved in water between 20 and 100° C., such as between 30 and 90° C., such as between 40 and 80° C., preferably between 40 and 60° C., such as at or near 40° C., 45° C., 50° C., 55° C. or 60° C. The drospirenone solution is added to the cyclodextrin solution and the obtained suspension is stirred at 20-30° C. for some hours, such as about 0.5 to 48 hours, then stirred at 2° C. for some hours. The crystallised product is isolated and dried. In an alternative process, the drospirenone solution is added to the cyclodextrin solution and the obtained suspension is stirred at temperatures below 25° C.
The inclusion complex may be prepared by methods described in or similar to those described in Examples 2, 3, 4, and 5.
The crystallised product may be washed with water, acetone and/or any other solvent in order to wash off non-complexed material. The solvent used to wash the crystallised product may be pre-cooled to below 25° C. This crystallised product may be dried over a drying agent such as P 2 O 5 or any other known to the person skilled in the art in a vacuum dessicator or cabinet for several hours or days. It may also be cooled in the dessicator during drying, or undergo spray drying or lyophillization.
A further objective of the invention is to provide a pharmaceutical composition comprising an inclusion complex of drospirenone and cyclodextrin as described supra together with one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may be adapted to be administered by oral, parental, mucosal, or topical, vaginal, subcutaneous or nasal administration. The composition may comprise from 0.1 mg to 10 mg of drospirenone, depending on its therapeutic application.
The drospirenone cyclodextrin inclusion complex may be used as a medicament. The drospirenone cyclodextrin inclusion complex may be used for the preparation of a pharmaceutical composition for female contraception or for the treatment of menopausal symptoms.
In suitable embodiments of the present invention, a pharmaceutical composition may comprise an inclusion complex between drospirenone and cyclodextrin and further comprise one or more therapeutically active substances. The therapeutically active substance is preferable a steroid. The therapeutically active substance may be complexed with cyclodextrin. Moreover, it may form part of an inclusion complex further comprising drospirenone. For instance, in the embodiment wherein drospirenone and cyclodextrin form an inclusion complex with a 1:2 or 1:3 molar ratio, respectively, said inclusion complex may further comprise a therapeutically active substance to form an inclusion complex with a 1:2: 1 or 1:3:1. Alternatively, said therapeutically active substance may be provide not as part of an inclusion complex. The pharmaceutical composition may comprise a drospirenone cyclodextrin inclusion complex, a therapeutically active substance such as estrogen or progestogen or a gestagen together with one or more pharmaceutically acceptable carriers or excipients.
Thus, one embodiment of the present invention is a three-component inclusion complex comprising drospirenone, one or more therapeutically active substances and cyclodextrin. The three-component complex may, for example, comprise drospirenone, cyclodextrin and a therapeutically active substance in molar ratio of 1:1:1, 1:2:1, 1:3:1, 2:2:1, 2:3:1, 2:3:2, 1:3:2. The molar ratio is limited in part by the size cavity of the cyclodextrin, by the nature of the active substance and by the size of moieties included into the cavity.
Three component complexes may be prepared by combining the therapeutically active substance in solid or solution form with either a solid or solution form of drospirenone, a solid or solution form of cyclodextrin, a solid mixture of cyclodextrin and drospirenone, or with a solution of cyclodextrin and drospirenone, namely the combined solution.
The entire disclosures of all applications, patents and publications, cited herein, and of U.S. Provisional Application Serial No. 60/256,483, filed Dec. 20, 2000, and of EP Application No. 00610134.9, filed Dec. 20, 2000, are hereby incorporated by reference.
BRIEF DESCRIPTION OF THE EXAMPLES
Example 1 compares the solubility of drospirenone in water with the solubility of a sample of an inclusion complex substantially consisting of a 1:1 molar ratio between β-cyclodextrin and drospirenone and to a sample consisting substantially of a 2:1 molar ratio between β-cyclodextrin and drospirenone. The example illustrates the increase in solubility of drospirenone by complexation with β-cyclodextrin. The example further discloses the stability of the 1:1 complex.
Examples 2 and 5 disclose two alternative methods for the preparation of a complex between drospirenone and γ-CD.
Examples 3 and 4 disclose two alternative methods for the preparation of a complex between drospirenone and β-CD.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 represents the structure of drospirenone and an embodiment of another component of the inclusion complex, cyclodextrin, namely β-cyclodextrin. β-cyclodextrin is a macrocycle consisting of 7 sugar units, whereas γ-cyclodextrin is a macrocycle consisting of 8 sugar units.
EXAMPLES
The foregoing and in the following examples are not a limitation upon the invention. In the examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
Example 1
Solubility of Drospirenone
The following data were obtained with the phase solubility diagram technique (PSD) In aqueous solutions at 20° C. The stability constants of the inclusion compound from β-CD and drospirenone are given.
Stability constant of the 1:1 complex
K 11 = 2.2 × 10 −4 M −1
Solubility of Drospirenone
S DP = 4.14 × 10 −5 mol/L (1.51 × 10 −2 g/L)
Solubility of 1:1 complex
S 1:1 = 3.88 × 10 −4 mol/L (0.516 g/L)
Solubility of 1:2 complex
S 1:2 = 3.79 × 10 −5 mol/L (0.1 g/L)
Example 2
Preparation of a Complex Between Drospirenone and γ-CD
30 mmol of the cyclodextrin are dissolved in 900 mL of water at 45° C. and, over the course of 30 min., 10 mmol of drospirenone, dissolved in 130 mL of ethanol are added dropwise. After washing with a further 5 mL of ethanol, cooling to room temperature, stirring at room temperature for 24 h and stirring in an ice bath (2° C.) for 4 h, the precipitate was filtered off with suction on a G4 frit. The resulting complex was then washed twice with 100 mL of ice water each time and once with 50 mL of ice-cooled acetone. It is then dried in a dessicator over phosphorous pentoxide.
Example 3
Preparation of a Complex Between Drospirenone and β-CD
24 mmol of the cyclodextrin are dissolved in 970 mL of water at 45° C. and, over the course of 30 min, 8 mmol of drospirenone, dissolved in 90 mL of ethanol are added dropwise. After washing with a further 5 mL of ethanol, cooling to room temperature, stirring at room temperature for 22 h and stirring in an ice bath (4° C.) for 3 h, the precipitate was filtered off with suction on a G4 frit. The resulting complex was then washed twice with 100 mL of ice water each time and twice with 50 mL of ice-cooled acetone. It is then dried in a dessicator over phosphorous pentoxide.
Example 4
Preparation of a Complex Between Drospirenone and β-CD
15.5 g of β-CD are dissolved in 1000 mL of water, heating if necessary. 1.468 g of drospirenone are weighed into the aqueous cyclodextrin solution. The suspension is stirred at room temperature for 72 h. It is then stirred at +2° C. for 3 h. The solid is filtered off with suction on a G4 frit and washed twice with 100 mL of water each time. The crystals are twice suspended in 50 mL of acetone and filtered off with suction each time. They are then washed with 100 mL of water. The moist crystals are dried in vacuo over phosphorous pentoxide.
Example 5
Preparation of a Complex Between Drospirenone and γ-CD
21.38 g of γ-CD are dissolved in 1000 mL of water, heating if necessary. 1.83 g of drospirenone are weighed into the aqueous cyclodextrin solution. The suspension is stirred at room temperature for 72 h. It is then stirred at +2° C. for 3 h. The solid is filtered off with suction on a G4 frit and washed twice with 100 mL of water each time. The crystals are twice suspended in 50 mL of acetone and filtered off with suction each time. They are then washed with 100 mL of water. The moist crystal are dried in vacuo over phosphorous pentoxide.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
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Described are inclusion complexes formed between cyclodextrin and drospirenone. In a specific embodiment of the invention, the cyclodextrin is β-cyclodextrin. The invention further relates to methods of providing such an inclusion complex, and to the use of said inclusion complex for improving the solubility of drospirenone, for providing pharmaceutical compositions, for use as a medicament in the treatment of symptoms associated with menopause and in female contraception.
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CROSS REFERENCES TO RELATED APPLICATIONS
[0001] U.S. Provisional Application for Patent No. 60/436,233, filed Dec. 26, 2002, with title, “System for Solid-Liquid Separation” which is hereby incorporated by reference. Applicant claims priority pursuant to 35 U.S.C. Par. 119(e)(1).
[0002] Statement as to rights to inventions made under federally sponsored research and development: Not applicable.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates generally to dewatering equipment and more particularly, to a system that semi-continuously filters both fibrous materials and particulate materials from slurries, producing a substantially dry filter cake. The system further deposits the cake in containers, and when required, returns the relatively clean filtrate to be reused.
[0005] 2. Brief Description of Prior Art
[0006] Solid-liquid separation is a major unit operation that exists in almost every flow scheme related to the chemical process industries, ore beneficiation, pharmaceutics, food, or water and waste treatment. The lack of cost effective equipment to handle these major unit operations and the enormous pollution problems caused by fluid production systems has resulted in industries abandoning many thousands of refuse ponds. The coal industry has created several hundred coal refuse slurry ponds holding an estimated 2 to 3 billion tons of discarded fine coal particles. Each year an estimated 30 million more tons are discarded into these waste ponds. Most of these slurry ponds are abandoned, un-monitored, and pose an enormous environmental hazard.
[0007] Existing methods of slurry management by industry using slurry ponds, concrete pools or plastic lined pools for slurry storing or processing are not environmentally sound. Tighter governmental monitoring of slurry ponds has brought about the need for active solid-liquid separation devices that are both economical and environmental effective. Prior art systems have not been effective. Many such prior art systems are not automated or continuous, or semi-continuous. Such prior art systems typically use disposable filter or cloth. Other systems may also use elastomeric diaphragms which limit the chamber size. Others apply heat or chemicals or both which reduce the reliability and raise the cost of operation. Centrifuges and belt presses have not been the answer in most cases. Some inventions use compression chambers that separate with an upper part and lower part that require hundreds of thousands pounds of force to hold the two parts together. Although these work for low throughputs, the design limits their applications and the cost per gallon slurry processed is high. Some use stacked multiple chambers increasing the complexity and manufacturing costs while reducing the reliability. Vacuum disc filters have proved unreliable, have low throughput, and fail to produce “dry” solids that meet industry standards. Others have tried the vacuum-atmosphere technique, with and without membranes, which has not been effective in creating “dry” solids.
[0008] Dewatering equipment can be used to clean up these environmental liabilities. The dewatering equipment needed must be of reasonable cost, non-labor intensive, reliable, adaptable to different slurries, and able to handle high throughput. It must make the disposal of or reuse of the treated materials both economical and environmental effective.
[0009] As will be seen from the subsequent description, the preferred embodiments of the present invention overcome short comings of the prior art.
SUMMARY OF THE INVENTION
[0010] More throughput for less cost while meeting industry “dry” solids standards is the principal objective of the present invention. Poiseuille's Law as applied to filter cakes confirms that the higher the pressure the faster the liquid flows through the filter cake. The present invention uses air pressure to squeeze the filter cake and dewater it. Air pressure is the optimum method for dewatering a uniformly distributed cake. It is more troublefree than methods using membranes or diaphragms and air moving through the cake helps to produce a substantially dry cake.
[0011] The design of the present invention allows the operator to adjust both the time intervals and amount of pressure for the cake buildup and for the cake dewatering. These variables are adjusted to optimize the dewatering cycle for maximum throughput per hour.
[0012] From the equation, pressure=force/area (P=F/A), to have enough pressure to perform the squeeze and have enough area for high throughput requires a very high force. The higher the force the costlier the equipment plus reliability and leaks become a problem. Unlike U.S. Pat. No. 5,573,667 that uses separable plate members that require up to one million pounds of force to hold the plates together during this squeeze, the present invention uses a fixed filter chamber with openings and sealing means at each end of the chamber for entrance and exit of a filter belt. The openings require very little force to actuate or keep closed during the squeeze cycle. Both structural find economical requirements limit the maximum width of each opening to between 4 and feet. As long as the width of the belt and the chamber width is of this optimum width (4 to 6 feet), the length of the chamber can vary for the job at hand and the cost of manufacturing the apparatus remains reasonable. For a four foot wide belt, the filter area can vary from 32 to 96 square feet. For extremely high throughputs, two or more chambers can be connected in parallel and operated by the same computer.
[0013] Keeping the filter belt narrow has several advantages. A long, narrow chamber is much easier to design and build to handle high pressures. An interior four foot filter belt grid requires a lot less structural strength than one eight foot wide. Four foot wide doors are also a lot less likely to warp under pressure than 8 foot doors. Further, uniform distribution of the solids on the filter belt is easier to achieve in a relatively narrow, rectangular chamber.
[0014] For different applications, only the length of the chamber changes; the doors, the belt washer, the rollers, the catch tray, are preferably for an approximate four foot wide filter belt. This all adds up to cost savings plus keeping the system narrow as discussed above also makes it easy to transport.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] [0015]FIG. 1 is a perspective partial sectional view of the present invention, a system for solid-liquid separation.
[0016] [0016]FIG. 2 is an enlarged side partial sectional view of the exit sealing means to the system's chamber.
[0017] [0017]FIG. 2A is an enlarged side partial sectional view of the exit sealing means of FIG. 2 in a closed position.
[0018] [0018]FIG. 2B is an enlarged cross-sectional view illustrating the filter belt, filter belt grid, and sealing shelf within the system's chamber.
[0019] [0019]FIG. 3 is an enlarged side view of the entrance sealing means to the system's chamber.
[0020] [0020]FIG. 4 is a schematic view of the present invention including optional equipment.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0021] In accordance with the present invention, a system for solid-liquid separation 10 is disclosed. The system 10 provides semi-continuous filtering of both fibrous materials and particulate materials from slurries, producing the required dry filter cake. The system 10 generally uses a fixed filter chamber member with openings at each end of the chamber for entrance and exit of a filter belt. The openings each include sealing means that require very little force to actuate, or keep closed during the squeeze cycle. In general, the present invention uses an air operated seal to seal the entrance opening for the filter belt, and a special gasket arrangement that seals the exit opening. Linear actuators known in the art are used to close the exit of the chamber for the cake buildup and squeeze cycles, and to open the exit for the discharge of the dry cake. These preferred embodiments save not only in the cost of operating the equipment, but in manufacturing the system 10 .
[0022] FIGS. 1 - 4 illustrate a preferred embodiment of the system for solid-liquid separation 10 made in accordance with the present invention. FIG. 1 is a perspective view of the system 10 . The system 10 includes a chamber member 12 having at least one entrance opening 20 and at least one exit opening 22 , for entrance and exit of a filter belt 30 . As shown in FIG. 1, the chamber 12 further having a top wall 12 A, and end walls 12 B that define an inner chamber 15 .
[0023] As shown in FIG. 2B, the chamber member 12 further includes an internal filter grid 31 positioned on a sealing shelf 32 that extends the perimeter of the filter belt grid 31 . In application, the filter belt 30 moves along the filter belt grid 31 within the chamber member 12 . In particular, the filter belt 30 is disposed on a first shelf 32 A of the sealing shelf 30 , and the filter belt grid 31 is disposed on a second shelf 32 B of the sealing shelf 32 .
[0024] The basic operating principle of the system 10 consists of three phases: In the first phase, slurry 100 (see FIG. 4) is pumped with a slurry pump 102 at a high rate into the chamber member 12 at the location designated “A” in FIG. 4. The slurry 100 collects (not shown) on the filter belt 30 within the chamber 15 . As the solids begin to build up on the belt 30 , the solids 110 become the main filter element, and a seal is formed between the filter belt 30 and the first shelf 32 A by the solids within the slurry 100 . Filtrate 115 is cleaned and recycled back for reuse. As the solids 110 become thicker and more dense, the speed of the filtrate 115 through the solids 110 slow to a point where it is more efficient to stop the slurry pump and do the squeeze. The second phase has air pressure 104 between two and six atmospheres supplied to ine chamber 15 . The squeeze from the pressure removes the remaining filtrate 115 from the solids 110 until the moisture reaches a specified level. Phase three consists of releasing the sealing means as will be discussed thereby opening the entrance and exit openings 20 , 22 , and turning the filter belt 30 . As the belt 30 turns over rollers 32 , the cake of solids 110 break up and is preferably deposited down a chute 35 (shown in FIG. 1) into all awaiting container (not shown). The filter belt 30 can move in and out of the chamber 15 of the chamber member 12 by manual cranking or, an electric motor(s) (not shown) can be used to turn the filter belt 30 . In the alternative, a continuous belt can be used.
[0025] [0025]FIG. 2 is an enlarged side view of the exit opening 22 and exit sealing means 22 A of the present invention. In particular, the exit sealing means 22 A includes a hinged door 40 hinged to an upper surface 23 adjacent the exit opening 22 using connections 41 known in the art. Linear actuators 45 are used to open and close the door 40 in relation to the exit opening 22 .
[0026] As shown in FIG. 2, the exit opening 22 in relation to the chamber member 12 is constructed having an angled opening designated as letter “B”, preferably a 60 degree angle opening. The door 40 includes an end 40 A. A first gasket 46 is affixed to the end 40 A of the door 40 and extends along a surface 46 A, and past horizontal gasket 48 . When the door 40 is in the closed position as shown in FIG. 2A, the surface 46 A is in sealing contact with the edges of the filter belt 30 .
[0027] The gasket 48 is affixed to the inside of the first gasket 46 . The gasket 48 is preferably disposed at a 35 degree angle. When the door 40 is in the closed position, the gasket 48 is in sealing contact with the top surface of the filter belt 30 . In the preferred embodiment, both the angle B of 60 degrees and the angle of 35 degrees of gasket 48 as described above are such as to minimize the wear of the gaskets and filter belt.
[0028] [0028]FIG. 3 is an enlarged view of the entrance opening 20 and entrance sealing means 20 A. FIG. 3 illustrates the sealing means 20 A in an open position. In particular, the chamber member 12 includes an angled projection member 50 that outwardly extends from the upper surface of the chamber member 12 . The projection member 50 having a top surface 50 A and a lower surface 50 B. A seal 52 is appropriately attached to the lower surface 50 B of the projection member 50 so that the seal 52 is disposed directly above the filter belt 130 at entrance slot 56 . The seal 52 extends the necessary distance past the edges of the filter belt 30 to secure a sealing at the belt edges. In the preferred embodiment, the seal 52 is an air operated seal known in the art.
[0029] As shown in FIG. 3, the entrance opening 20 in relation to the chamber member 12 is constructed having an angle opening designated as letter “C”, preferably a 45 degree angle. Further, for proper sealing, the seal 52 is attached to the projection member 50 so that a midpoint 54 is positioned directly above the entrance slot 56 .
[0030] In application, the seal 52 shown deflated in FIG. 3, can be expanded so that a compression seal exists between the seal 52 and the filter belt 30 and in particular, where the midpoint 54 of the projection member 50 contacts the entrance slot 56 .
[0031] [0031]FIG. 1 shows the generally rectangular shaped chamber member 12 that the inventor has found optimum. It is imperative to have as wide a filter belt 30 as possible and still keep the cost of the apparatus reasonable. At four feet, the wall thickness and costs are reasonable. Any wider than four feet, the cost starts increasing quickly. If more throughput is required, the chamber member 12 can easily be made longer up to approximately twenty-four feet. Ninety-six square feet of filter area can process thousands of gallons of normal slurry per hour. It is obvious that the cost of the apparatus per foot filter area goes down as the chamber member 12 gets larger.
[0032] From the equation, pressure=force/area (P=F/A) one can see that to have enough pressure to do the squeeze in a reasonable time and enough area for the required throughput, one must use an enormous amount of force. Force is directly related to expense, therefore it appears to be a very expensive concept. For example, the force required to hold two chambers together while applying 100 pounds per square inch of pressure on 100 square feet of filter area is almost 1.5 million pounds of force. U.S. Pat. No. 5,573,667 uses massive hydraulic presses and a super structure made of massive amounts of material to perform the job. Knowing force (F) is the variable in the equation that is more directly a function of the cost of the equipment, the present inventor designed a system that uses said fixed chamber member 12 with the openings 20 , 22 for the entrance of the filter belt 30 into the chamber 15 , and to remove the dry solids 110 from the chamber 15 .
[0033] The described sealing means 20 A, 22 A, require basically no energy to sealingly hold closed during the slurry pumping phase or the squeeze phase, and little energy to move to the open or closed position. Preferably, opening the entrance sealing means 20 A is preferably just enough for the filter belt 30 to enter the chamber 15 through the entrance opening 20 . Likewise, the door 40 at the exit opening 22 is minimally opened and closed as required. In particular, opening the exit sealing means 22 A so that the filter belt 30 and dry solids 110 can exit the chamber 15 through the exit opening 22 . By using an air operated seal 52 to seal the entrance opening 20 as discussed above, and using the linear actuators 45 with the first and second gasket 46 , 48 arrangement for sealing the exit opening 22 , one experienced in the art can see that the system 10 is easily automated.
[0034] The present invention is designed to be as reliable and trouble free as possible with few moving parts. The application of the air operated seal 52 to form an airtight seal on the filter belt 30 at the entrance opening 20 of the chamber 12 as discussed, is the preferred method. The unique method of having the air seal 52 attached to the angled projection member 50 so that the seal 52 activates at an angle as shown in FIG. 3, reduces the internal torque on the seal, increases the sealing area, and minimizes wear therefore increasing reliability.
[0035] An important way this invention minimizes wear and improves reliability is by having the exit sealing means 22 A close and seal to the filter belt 30 at an angle as discussed. Another aspect of this invention is the unique application for sealing the edges 31 of the filter belt 30 . When the exit sealing means 22 A is in the closed position, the gasket 48 affixed to the first gasket 46 of the door 40 so that surface 46 A extends below the edge of the filter belt 30 so when the door 40 is closed, the peal squeezes towards the filter belt 30 sealing the edges 31 .
[0036] Another important aspect of the present invention is the method used to evenly distribute the solids as a buildup on the filter belt 30 . The preferred embodiment uses a distribution manifold 13 with an internal disperser 14 disposed within the chamber member 12 to supply the slurry to the contents within the chamber 15 . Without an evenly distributed solid cake, the air pressure will not effectively squeeze the filtrate from the cake.
[0037] After the slurry 100 is pumped into the chamber 15 and the solid cake 110 is built up to the required thickness, the present invention has a method for drawing the remaining slurry left on top of the cake 110 back to the slurry mixing tank using a pump 126 , as shown in FIG. 4. This conserves energy, reduces the squeeze time, third increases the throughput per hour.
[0038] Further detailing the operation of the system 10 with references to FIG. 4, slurry 100 is brought into mixer tank 200 . The slurry can be combined with filtrate introduced by valve 202 and recycled belt cleaning water from pump 128 . When the valve 204 opens, the slurry mix can flow through pump 102 to the valve 206 . Prior to opening valve 206 , a precoat feed 208 can supply belt precoat material through valve 210 . The precoat material can be mixed with water from a supply 212 through valve 216 . The belt precoat mixes with the water in mixer 220 and can flow through valves 224 and 206 to precoat the belt 30 within chamber 12 . The precoat material makes the belt 30 easier to clean for example depending upon the slurry the system 10 is used on. Slurry material can then flow through the input A and manifold 13 onto the belt 30 until the thickness of the solids cake 110 reaches the point where slurry flow falls below a desired level. Air pressure from compressed air tank 104 is applied to chamber 12 through the valve 230 . The pressure will squeeze the filtering material into a relative dry cake 110 . The valve 230 is closed and chamber 12 is opened so that belt 30 can be moved by rollers 32 . Cake 110 will break off the belt 30 when it passes over a roller 32 . Any material stuck to the belt 30 can be washed off in belt washer 125 using water from supply 212 through the valve 232 and/or compressed air from tank 104 through valve 234 . The water and air in belt washer 125 can be applied to the opposite side of the belt from where material was caked to aid in the removal. The valves, belt and seals shown can be controlled manually or can be operated and controlled automatically by an automatic controller such as a programmable controller not shown.
[0039] [0039]FIG. 4 further illustrates the system 10 with optional equipment. Some slurries are more gelatinous and require belt precoating to help the solids separate from the belt 30 . Other slurries require body-aid and some require precoating and body-aid. Some industries have value in the solids and require one or more cake wash cycles. A belt washer 125 is necessary to clean the filter belt 30 in certain applications. Other slurries require only the combined belt cleaning properties of an air pressure cleaning rod (not shown) and the top edge of the chute 35 as a scraper. After testing the slurry, a custom dewatering apparatus is built with the options necessitated by that specific slurry.
[0040] From the foregoing, it is seen that the present invention provides an effective and efficient means for solid-liquid separation that is cost effective and easily transportable.
[0041] Although the description above contains many specificities, these should not be construed as limiting the scope of the invention but is merely providing illustrations of the presently preferred embodiments of the present invention.
[0042] Thus the scope of the invention should be determined by the appended claims in the formal application and their legal equivalents, rather than by the examples given.
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A system for use in filtering a slurry using air pressure to squeeze the slurry material and dewatering it. The system including a source of slurry, a chamber, a filter belt that passes through the chamber, a manifold inlet supplying the slurry to a first side of the filter belt to form a uniform moist cake of the filter material, an inlet seal and an outlet seal to seal a belt inlet nd a belt outlet formed on the chamber, and a source of the pressurized air selectively applicable to the chamber to dry the moist cake of filtered material.
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FIELD OF THE INVENTION
The present invention relates to dispensing devices, and more particularly to a hand-held caulk dispensing gun.
DESCRIPTION OF THE BACKGROUND
Caulking guns are used to dispense a wide variety of fluid compositions such as urethane, vinyl, polyester, epoxy and other plastics. These compositions are often very dense, yet the caulking gun must be capable of applying the composition over a wide range of volumetric flow rates. In order to achieve higher flow rates, prior art caulking guns were necessarily small in size. Otherwise, the force required to operate the caulking gun would exceed the capabilities of the operator. Consequently, complex gear-drives and pneumatic caulking guns were developed to overcome the problem. However, these improved caulking guns share a common characteristic. They are very expensive to manufacture and produce. There is a clear demand for an inexpensive hand-held caulking gun capable of delivering a dense composition at a high delivery volume and flow rate. U.S. Pat. No. 4,081,112 issued to Chang addresses the demand. The Chang caulking gun positions the trigger pivot and trigger drive grip engagement above the plunger shaft. This improvement increases the leverage obtainable by a hand operated trigger and allows delivery of the composition at a higher volume and flow rate than was previously possible in a hand-held caulking gun. Moreover, the improvement can be accomplished at no additional cost.
Nevertheless, there is an ever increasing demand for a hand-operated caulking gun having more power and improved features.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide an improved caulking gun capable of delivering a dense composition at a high volume and flow rate.
It is another object of the invention to provide the above-described caulking gun at a minimum manufacturing expense.
It is still another object of the present invention to incorporate the above-described advantages in a twin cylinder caulk dispenser for use in delivering complementary compositions such as epoxy resin and hardener.
It is yet another object of the present invention to provide a caulk dispenser which is convenient to use, and which minimizes hand fatigue resulting from prolonged use.
According to the present invention, the above described and other objects are accomplished by providing a frame, a plunger including a plunger shaft for forwardly urging a caulking composition, plunger driving means including a housing having a downwardly extending handle, a first grip enclosed within the housing, said first grip encircling the plunger shaft and protruding upwardly beyond the plunger shaft to a location proximate an upper portion of the housing, a trigger pivoted to the housing and extending upwardly within the housing to a trigger pivot located above the plunger shaft, a bearing bit mounted on a portion of said trigger above the pivot, said bearing bit operatively engaging the upward protrusion of the first grip, and the first grip being driven by the bearing bit for advancing the plunger, a first compression spring oppositely biasing the first grip against the operative engagement with the bearing bit, and plunger pressure retaining means including a second grip and second spring, the second grip biased by the second spring and having a portion operable for releasing plunger pressure whereby the plunger can be manually retracted.
BRIEF DESCRIPTION OF THE DRAWINGS
Other features and advantages of the present invention become apparent from the following detailed description of preferred embodiments and certain modifications thereof when taken together with accompanying drawings, in which:
FIG. 1 is a perspective view of a caulking gun according to one embodiment of the present invention.
FIG. 2 is a break-away view of the internal assembly of a caulk dispenser having an adjustable bearing assembly in accordance with the embodiment shown in FIG. 1.
FIG. 3 is a perspective view of the adjustable bearing assembly of FIG. 2.
FIG. 4 is an assembly diagram of the adjustable bearing assembly of FIG. 2.
FIG. 5 is a break-away view of caulking gun of FIG. 1 showing a trigger stop mechanism according to the present invention.
FIG. 6 is a bottom view of the trigger stop mechanism of FIG. 5.
FIG. 7 is a perspective view of a dual cylinder caulk dispenser according to another embodiment of the present invention.
FIG. 8 is a break-away view of the caulking gun of FIG. 7 showing the improved drive mechanism according to the present invention.
FIG. 9 is a detailed diagram of the piston assembly of FIG. 7.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 is a perspective view of a manually operated caulking gun according to the present invention. The caulking gun includes a plunger 50 having a plunger shaft 55 which is driven by an improved plunger drive assembly. The drive assembly includes a housing 80, and a trigger 10 pivoted at a screw hinge 40 located piston above shaft 55. As described in U.S. Pat. No. 4,081,112 issued to Chang, screw hinge 40 is located above piston rod 50 to increase the trigger leverage. The drive assembly further includes a bearing assembly 30 located on a portion 20 of trigger 10 which extends above screw hinge 40. In addition, a trigger stop mechanism 60 is provided on downwardly extending handle 90 to adjust the arc of trigger 10 for reducing hand fatigue.
FIG. 2 shows a break-away view of the improved drive assembly of FIG. 1. Plunger shaft 55 extends through, and is carried by housing 80. Trigger 10 extends upwardly into housing 80, straddles plunger shaft 55, and is pivotally fixed to housing 80 at a screw hinge 40 located above plunger shaft 55. A portion 20 of trigger 10 extends past screw hinge 40. Bearing assembly 30 includes a bearing bit 100 adjustably secured by set screw 110 to the upwardly extending portion 20 of trigger 10. A first gripping member 120 is carried by plunger shaft 55 and is biased away from the left wall of housing 80 and into bearing bit 100 by compression spring 130. The resilient bias is imparted to trigger 10 through bearing bit 100. An opposite resilient bias is imparted on trigger 10 by compression spring 135. A second grip 140 extends downwardly from the top of housing 80 and straddles plunger shaft 55. Grip 140 pivots at the top of housing 80 and is outwardly biased by compression spring 150.
In operation, trigger 10 is depressed and pivots about screw 20 hinge 40. Bearing bit, 100, which is carried on the upper portion 20 of trigger 10, is forced against grip 120 as trigger 10 is depressed. As grip 120 is pressed forward, it engages plunger shaft 55 and causes plunger shaft 55 to be driven forward through housing 80. As trigger 10 is released, it is biased back to its original position by compression spring 135. Likewise, grip 120 returns to its original position as a result of spring 130. However, grip 140 engages plunger shaft 55 to prevent the shaft from back-sliding. The above-described operation is repeated to drive the plunger shaft 55 incrementally forward until the caulk cylinder is depleted and/or the operator desires to stop. At this point the portion of grip 140 extending downwardly below plunger shaft 55 can be depressed, thereby releasing all pressure on plunger shaft 55. An operator may grasp knob 160 for convenient extraction of plunger 50 from a caulk cylinder (not shown). The caulk cylinder can then be easily removed and discarded.
FIG. 3 and FIG. 4 give a more detailed illustration of bearing bit 100 and its mounting. Bearing bit 100 is a low friction insert which may be formed of brass, oil impregnated sintered metal, a polymer, or any other known low-friction material. Bearing bit 100 slides across the face of grip 120 as trigger 10 is pivoted. The composition and shape of bearing bit 100 are carefully chosen to minimize friction despite the perpendicular caulking force exerted between grip 120 and bearing bit 100.
Bearing bit 100 is mounted on an upper portion 20 of trigger 10 which extends above screw hinge 40. Elongated slot 170 is formed through trigger 10, and set screw 110 is threaded through slot 170 into the rear of bearing bit 100. The head of set screw 110 straddles the elongated slot 170. This way, when set screw 110 is tightened, bearing bit 100 is secured against trigger 10. The position of bearing bit 100 can be adjusted upwardly or downwardly along the upper portion of trigger 10 depending on the seating of set screw 110 within elongated slot 170. This adjustment allows the leverage of trigger 10 against grip 120 to be increased or decreased accordingly. If bearing bit 100 is seated low on the upper portion 20 of trigger 10, then the leverage is maximized and a greater force can be exerted on plunger shaft 55. Conversely, if bearing bit 100 is seated high upon trigger 10, then the leverage is minimized and plunger shaft 55 can be moved in larger increments. Additionally, an index may be provided adjacent to slot 170 for facilitating the positioning of bearing bit 100. Set screw 110 can be aligned with the index to achieve a predetermined leverage.
When an operator desires to cease dispensing the composition, he may depress grip 140. This frees the plunger shaft 55, thereby releasing the compressive force.
The invention may be provided with a bore hole 25, as shown in FIGS. 1 and 2, through one side of handle 90. The conventional cartridge tip provided on a caulk cylinder may be inserted through bore hole 25, and the tip may be severed by pivoting trigger 10 against handle 90. Thus, the caulk dispenser of the present invention provides an additional convenience by severing the tip of a new caulk cylinder.
FIGS. 5 and 6 detail a trigger stop mechanism 60 which may be used to limit the arc of trigger 10 when depressed. It has been found that shortening the arc of trigger 10 helps to alleviate hand fatigue. Trigger stop 60 comprises a knob 190 mounted on a stem 200 which passes through and is carried by handle 90. The rotation of knob 190 causes rotation of stem 200. A strut 220 is mounted on stem 200 inside handle 90. Rotation of knob 190 causes strut 220 to pivot around stem 200. A pin 240 extends from the opposite end of strut 220 toward one side of handle 90. Pin 240 fits within one of a number of holes 230 which are equidistant from stem 200. A compression spring 210 biases strut 220 such that pin 240 will remain seated in one of the holes 230. Knob 190 can be pulled away from handle 90 and rotated in order to extract and position pin 240 in another of the holes 230. In this manner, an operator can align strut 220 in different angles with respect to trigger 90. The arc in which trigger 90 is free to swing is determined by the alignment of strut 220. By limiting the arc of trigger 90, an operator can reduce hand fatigue when dispensing a large amount of caulk over time.
FIG. 7 shows another embodiment of the invention in which the above-described features are incorporated in a dual cylinder caulking gun. The dual cylinder caulking gun operates with two parallely spaced plunger shafts 260 and 270 which are joined at one end. A housing 280 carries both plunger shafts 260 and 270, which both extend through and are carried by housing 280. Frame 290 is designed to accommodate a twin cartridge for dispensing compositions which must be mixed immediately prior to application. The resin and hardener which mix to form epoxy cement are typical examples of such compositions.
FIG. 8 shows a break-away view of the improved drive assembly of FIG. 1 adapted for use in a dual cylinder caulking gun. Trigger 300 extends upwardly into housing 280, straddles the lower plunger shaft 270, and is pivotally fixed to housing 280 at a screw hinge 310 located above lower plunger shaft 270. A portion 305 of trigger 300 extends past screw hinge 310 toward upper plunger shaft 260. A first gripping member 320 is carried by upper plunger shaft 260 and is biased away from the left wall of housing 280 by compression spring 330. The resilient bias is imparted to trigger 300. An identical bearing assembly 30 as shown in FIGS. 1-4 may also be incorporated in the dual cylinder caulking gun. Compression spring 340 imparts an opposing resilient bias to trigger 300. A second grip 350 extends downwardly from inside housing 280, straddles lower plunger shaft 270, and protrudes upwardly outside housing 280.
In operation, trigger 300 is depressed and pivots about screw hinge 310. The upper portion 305 of trigger 300, including bearing assembly 30, drives grip 320 as trigger 300 is depressed. As grip 320 is driven forward it engages upper plunger shaft 260 and drives both shafts 270 and 260 forward through housing 280. As trigger 300 is released, it is biased back to its original position by compression spring 340. Likewise, grip 320 returns to its original position as a result of spring 330. However, grip 350 will engage plunger shaft 270 to prevent the shafts 260 and 270 from back-sliding. The above-described operation is repeated to drive both plunger shafts 270 and 260 incrementally forward until the caulk cylinder is depleted and/or the operator desires to stop. At this point grip 350 can be depressed to release all pressure on plunger shaft 270. An operator may grasp the junction of plunger shafts 260 and 270 for convenient extraction from a twin caulk cylinder (not shown). The caulk cylinder can then be easily removed and discarded.
By operating directly on upper plunger shaft 280, the drive mechanism of the present invention operates more easily than prior art dual cylinder caulking guns, yet the manufacturing costs are lower.
In addition, a twin caulk cartridge may be secured in place by tightening screw 400 which is threaded into the left wall of housing 280. The head of screw 400 abuts the caulk cylinder and, when extended, secures the cylinder against frame 290.
Snap-on piston assemblies 450 are also provided at the ends of plunger shafts 260 and 270.
FIG. 9 illustrates a snap-on piston assembly 450 in more detail. Piston assembly 450 includes a piston 455, and a hollow cylindrical base 460 on which piston 455 is mounted. The mid-section of base 460 is defined by a reduced diameter channel. A small bore hole 465 extends from the outer periphery of the channel through a wall of base 460 to the hollow thereof. The diameter of bore hole 465 is tapered to provide a seating for a small ball bearing 510. Ball bearing 510 sits within bore hole 465 such that the section of the periphery of ball bearing 510 extends slightly into the hollow of base 460. A compression ring 520 fits over ball bearing 510 and sits flush within the recessed channel of base 460. Compression ring 520 biases ball bearing 510 towards the hollow of base 460. An annular groove 530 is cut into the end of each plunger shaft. When the plunger shaft is fully inserted within base 460, ball bearing 510 extends into groove 530 such that piston 455 is releasibly locked on the end of the plunger shaft. A sharp pull on piston 455 will overcome the compressive force of band 520 and piston 455 can be removed from the shaft. Many shapes and sizes of pistons 455 may be easily interchanged with this assembly in order to accommodate the various twin caulk cartridges now available.
Various modifications and alterations of this invention will be apparent to those skilled ion the art without departing from the spirit and scope of the invention.
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An improved single and double cylinder hand-operated caulking gun having a direct plunger drive mechanism including a bearing assembly for increasing trigger leverage to allow delivery of a dense composition at a high volume and flow rate. The caulking gun of the present invention includes an adjustable trigger stop for minimizing hand fatigue during prolonged use, quick-release pistons, and a dual-cartridge restraining screw.
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BACKGROUND OF THE INVENTION
This invention relates to organopolysiloxane compositions having improved flame retardant properties. More particularly, this invention is concerned with a composition of matter which, in the cured state, exhibits improved flame retardant properties and which comprises, (1) an organopolysiloxane gum convertible to the cured, solid, elastic state and consisting essentially of silicon atoms, oxygen atoms and organic groups selected from the class consisting of methyl radicals, aromatic radicals selected from the class consisting of aryl and halogenated aryl radicals, vinyl radicals, lower alkyl radicals, lower cyanoalkyl radicals and lower haloalkyl radicals, (2) a finely divided inorganic filler, (3) a platinum compound or platinum and (4) and various effective amounts of hydrated alumina, fumed titanium dioxide, and magnesium oxide, in combination.
A method for improving the flame retardancy of a silicone rubber is shown in U.S. Pat. No. 3,514,424, Nobel et al, where a platinum compound or platinum is combined with other components of a silicone rubber to impart flame retardancy. While the addition of platinum or platinum compound does improve the flame retardancy of silicone rubbers and is entirely adequate for most uses, the rubbers produced according to the Noble et al Patent are not as flame retardant as might be desired.
U.S. Pat. No. 3,734,877, Christie, discloses a flame retardant composition consisting essentially of a silicone elastomer and an appropriate filler in combination with effective amounts of triphenyl phosphite. It has been found that the addition of triphenyl phosphite is not required for the silicone compositions of the present invention.
Other flame resistant compositions are disclosed in U.S. Pat. No. 3,635,874--Laur, and U.S. Pat. No. 3,652,488--Harder. Both patents disclose a silicone elastomer stock as well as inorganic filler, platinum and carbon black. The Laur composition further contains 0.5 to 100 parts by weight of fume titanium dioxide.
The composition of the present invention is superior to those disclosed above in that it does not require the addition of such pigments as carbon black and fume titanium dioxide in order to provide outstanding flame retardant characteristics, especially when measured by the rigorous 60 second Burn test. Of course, the flame retardant properties of these pigments can be utilized if desired.
To the extent that the above-identified patents disclose compositions and methods of compounding silicone elastomers, especially those having flame resistant characteristics, they are hereby incorporated by reference.
The silicone compositions of the present invention are particularly useful for forming silicone rubber products, which meet or surpass Federal Aviation Regulations for flame retardancy when such silicone rubber products are utilized in aircraft. As is well-known, aircraft materials must meet rigorous flamability testing procedures before they can be incorporated into the aircraft. Various tests are utilized to demonstrate the compliance of aircraft materials with FAA regulations for flamability characteristics and often the air worthiness certification of an aircraft can depend in great part upon the ability of raw materials to meet these rigorous standards.
Accordingly, there has been developed what will be called a 60-Second Burn Test which demonstrates the superior flame retardant characteristics of the silicone rubber compositions of the present invention. Specimen dimensions are 3×12×0.075±0.005 inches. A Bunsen or Tirrill gas burner having an inside diameter tube of approximately, 0.375 inches is utilized. The gas for the ignition source has an approximate composition of 55% hydrogen, 24% methane, 3% ethane and 18% carbon monoxide and has an approximate specific gravity of 0.365 (air=1) and an approximate BTU content of 540 per cubic ft. at 21° C. Test specimens are conditioned prior to testing by exposure to an atmosphere of approximately 70° F. and a relative humidity of 50% for a minimum of 24 hours.
The 60-Second Burn Test takes place in a draft-free cabinet wherein the lighted gas burner is adjusted to a flame height of approximately 1.5 inches. The temperature of the gas flame is measured by a thermocouple at approximately 0.75 in. above the burner orifice. A temperature between 1500° and 2000° F. is preferred. The specimen to be tested is mounted vertically and its bottom edge is flush with the bottom edge of the holding clamp. A timer is started immediately when the burner is brought into position below the sample at a point approximately 0.75 in. above the end of the burner orifice. The flame is held directly beneath this point for 60±0.5 seconds whereupon it is withdrawn. Timing is continued until the flame on the specimen goes out. The specimen should be considered "self-extinguished" if the flame goes out before reaching the top of the specimen. The term "self extinguishing time" will therefore be the recording time minus the 60-second ignition period.
It is therefore an object of the present invention to provide a curable silicone composition having superior flame resistant characteristics.
It is another object to provide a composition which surpasses the rigorous 60-Second Burn Test.
It is another object to provide a composition having flame resistant characteristics yet does not require the use of a carbon black pigment.
It is a further object to provide methods for producing such flame resistant curable silicone compositions.
SUMMARY OF THE INVENTION
The composition of the present invention is curable to a silicone rubber product which exhibits improved flame retardancy and tear strength and comprises; (A) 100 parts by weight of a base compound comprising a polydiorganosiloxane gum or blend of such gums having a viscosity of 1,000,000 to 200,000,000 centipoise at 25° C. and having an average unit formula of R a SiO 4-a/2 , wherein R is a monovalent substituted or unsubstituted hydrocarbon radical selected from the class consisting of methyl, vinyl and phenyl radicals, a is approximately 1.98 to 2.05, and wherein approximately 0 to 5.0 mole percent of the total organic groups are vinyl radicals; (B) 0.01 to 250 parts per million platinum; (C) 1.0 to 20 parts by weight hydrated alumina and (D) 0.001 to 2.0 parts by weight magnesium oxide. The composition of the present invention can also optionally include from 0.001 to 10 parts by weight of fumed titanium dioxide with good results.
The composition described above is curable to a silicone rubber when it is catalyzed and cured by means well-known in the art. For example, effective amounts of organic peroxides, as will be described below, are often utilized. The cured product of the present invention will then exhibit the improved flame retardancy and tear strength characteristics desired in a fabricated silicone rubber product. Various process aids for providing efficient milling and mixing of the ingredients and various fillers such as extending fillers and heat resistant fillers, as will be described below, may also be included.
The present invention also encompasses the process for providing a silicone composition which is curable to a silicone rubber exhibiting improved flame retardancy and tear strength wherein said process comprises the steps of compounding the various necessary and optional ingredients according to the process parameters which will be described below.
DESCRIPTION OF THE INVENTION
In producing the silicone rubber composition of the present invention there may be utilized any of the highly reinforcing type filler materials customarily employed in the production of elastomers. Preferably, these are inorganic compounds or combinations thereof. Especially preferable are the finely divided silica base fillers of the highly reinforcing type which are characterized by a particle diameter of less than 500 millimicrons and by surface areas of greater than 50 square meters per gram. Other inorganic filler materials may be employed alone or in combination with the preferred fillers with good results. Such filler materials are titanium dioxide, iron oxide, aluminum oxide as well as the inorganic filler materials known as inert fillers which may include, among others, diatomaceous earth, calcium carbonate, and quartz which will all may be employed in combination with the highly reinforcing silica fillers to improve the tensile strength or the hardness of the elastomeric product. Other examples of suitable fillers are diatomaceous silica, aluminum silicate, zinc oxide, zirconium silicate, barrium sulfate, zinc sulfide, aluminum silicate and finely divided silica having surface-bonded alkoxy groups.
The present compositions ordinarily employ 10 to 100% by weight (based upon the polysiloxane gum) of the filler and preferably 20 to 60% by weight.
There is also employed in the present composition up to 25 percent and preferably 5 to 15 percent by weight (based on the polydiorganosiloxane gum) of a process aid for preventing the gum and the filler mixture from structuring prior to curing and after compounding. One example of such a process aid is a compound of the formula, ##STR1## where R is a member selected from the class consisting of methyl, and phenyl, X is a member selected from the class consisting of --OH, --NH 2 or --OR', where R' is methyl or ethyl, n has a value of from 2 to 4, inclusive, and b is a whole number equal to from 0 to 10, inclusive. Further details as to the properties, as well as the method of preparation of the compound of formula (3), are to be found in the disclosure of Martellock U.S. Pat. No. 3,464,945, which is hereby incorporated by reference.
The process aid may also be a dihydrocarbon-substituted polysiloxane oil having a hydrocarbon substituent to silicon atom ratio of from 1.6 to 2.0 and whose hydrocarbon substituents comprise at least one member selected from the class consisting of methyl, ethyl, vinyl allyl, cyclohexenyl and phenyl groups, said polysiloxane oil comprising polysiloxane molecules containing an average of from one to two lower alkoxy groups bonded to each of the terminal silicon atoms where the alkoxy groups are selected from the class consisting of methoxy, ethoxy, propoxy and butoxy.
Preparation of the alkoxy-containing hydrocarbon-substituted polysiloxane oils that can be employed as a process aid in the present invention can be carried out by producing one or more types of cyclic dihydrocarbon-substituted polysiloxanes from one or more types of dihydrocarbon-substituted dichlorosilanes as is well-known in the art. One or more types of cyclic siloxanes so produced are mixed with the pre-determined amounts of a dihydrocarbon-substituted dialkoxysilane and the mixture is subjected to an equilibration treatment under controlled conditions to produce the desired alkoxy endblocked hydrocarbon-substituted linear polysiloxane oil.
The alkoxy-containing hydrocarbon-substituted polysiloxane oils suitable for use in the present invention are relatively low molecular weight polysiloxane oils whose polymer chains have at least four and as much as thirty-five and more dihydrocarbon siloxy units per molecule. The polysiloxane oils preferably have an average of at least one and not more than two alkoxy groups bonded to each of the terminal silicon atoms of the molecule. A more detailed disclosure of the alkoxy end-blocked polysiloxane process aids, as well as their method of preparation, is to be found in the disclosure of Fekete, U.S. Pat. No. 2,954,357, which is hereby incorporated into this specification by reference.
There may also be used as a process aid hydroxylated organosilanes which contain from one silicon-bonded hydroxyl group per 70 silicon atoms to two silicon-bonded hydroxyls per silicon atom and contains from 1.9 to 2.1 hydrocarbon radicals per silicon atom. The remaining valences o the silicon atom are satisfied by oxygen atoms. The hydroxylated materials include both monomers such as diphenylsilanediol and polymeric materials which contain two silicon-bonded OH groups in the molecule. In addition, the hydroxylated organosilane may be a mixture of hydroxyl-containing siloxanes and completely condensed siloxanes.
The hydroxylated siloxanes may be prepared by any suitable method, such as heating said siloxanes with steam under pressure at temperatures of about 120° C. or hydrolyzing silanes of the formula R n SiX 4-n where X is any hydrolyzable group such as Cl, OR, H, --OOR and R is a monovalent hydrocarbon radical. The former method is preferred for the preparation of those hydroxylated materials in which the hydrocarbon radicals are alkyl, while the latter method is best for the siloxanes in which hydrocarbon radicals are monocyclicaryl hydrocarbon radicals. Further, detailed information as to the hydroxylated organosiloxanes which may be used as process aids is to be found in Konkle et al U.S. Pat. No. 2,890,188, the disclosure of which is incorporated into this application by reference.
Any of the above process aids may be used alone or mixtures thereof may be used in the above-defined concentrations. Further, other suitable process aids may also be used in the silicone rubber compositions of the present invention.
The curing of the silicone rubber composition of the present invention can be effected by chemical vulcanizing agents or by high energy electron radiation. More often, chemical vulcanizing agents are employed for the curing operation and any of the conventional curing agents can be employed. The preferred curing agents are organic peroxides conventionally used to cure silicone elastomers. Especially suitable are the dialkyl peroxides which may have the structural formulas, ##STR2## wherein R represents the same alkyl group throughout, or alkyl groups of two or more different types and n is two or a larger integer.
Among the specific peroxide curing catalysts that are preferred are di-tertiary-butyl peroxide, tertiarybutyltriethylmethyl peroxide, 2,2-bis(t-butylperoxy)diisopropyl benzene and di-tertiary alkyl peroxide such as dicumyl peroxide. Other suitable peroxide catalysts which effect curing through saturated as well as unsaturated hydrocarbon groups on the silicon chain are aryl peroxides which include benzoyl peroxides, mixed alkyl-aryl peroxides which include tertiary-butyl perbenzoate, chloroacyl peroxides such as 2,4-dichlorobenzoyl peroxide, monochlorobenzoyl peroxide, benzoyl peroxide, etc. Generally, 0.1-8 percent of said peroxide, by weight of the polydiorganosiloxane gum is used to cure the silicone rubber composition and preferably 0.5-3.0 percent by weight.
There also can incorporated into the present silicone rubber composition pigments and heat stabilizers, such as iron oxides, carbon black, rare earth octoates, urethanes, etc.
In the practice of the invention, the present polysiloxane composition is produced by mixing the organopolysiloxane polymer, the silica or other types of filler and the process aid. After this mixture is formed, the flame retardant ingredients and the peroxide catalyst are mixed into the composition. At this point there may be added an iron oxide or a pigment. The order of addition of the latter ingredients is not critical, it is only important that the organopolysiloxane gum, the filler and the process aid be mixed together first before the other ingredients are added. The other ingredients, such as the peroxide curing catalysts and the flame retardant may then be added in whatever order is desired. The various ingredients in the mixture can be blended together by use of standard rubber mixing equipment, such as doughmixer, rubber mill, Waring blender and the like. One procedure, for example, is to add the inorganic filler to the polymer gum while it is being milled, followed by the addition of the process aid and then adding the fiber, organic additive compound, peroxide curing catalyst and the other additional ingredients as desired. Another procedure that can be employed is to doughmix the polymer and the inorganic filler, the process aid and the peroxide curing catalyst while it is being milled on the rubber mill and then adding the other ingredients thereafter. The nature and amount of the particular ingredients utilized and the manner of blending would be known to those skilled in the art in order to produce the desired cured product. To form the organopolysiloxane, the polymer, inorganic filler and the process aid which is optional, are added in a doughmixer and after the mixture is complete, the mixture is put on a mill. While it is on the mill there is added to the mixture the peroxide curing catalyst and the flame retardant additive compounds in any desired order. The milled sheets are then cured in a manner well-known in the art. The organopolysiloxane composition can be converted to the cured product by heating at temperatures in the range of 80° C. to 650° C., depending upon the nature of the curing catalyst, duration of cure, the amount and type of filler, etc., as well as the amount of the other ingredients. The direct conversion of the polysiloxane composition to the cured product can be effected as a result of the conditions normally utilized during conventional molding, extrusion and calendering operations. For example, depending upon the curing catalyst used, the temperature from 80° to 300° C. can be employed for compression and transfer molding.
Hot air curing at the temperatures of from 100° C. to 640° C. or steam vulcanization at temperatures from 110° C. to 2.0° C. can be employed for periods from 5 to 10 minutes, or a matter of seconds. The sheets can be calendered or milled first and then press-cured at 200°-400° C. for 30 seconds to 10 minutes or passed into an oven where they can be air heated to a desired temperature range of 100° C. to 300° C.
The platinum-containing material may be any of the materials generally utilized in SiH+Si-olefin reactions. Among the forms of this platinum are elemental platinum as shown in U.S. Pat. No. 2,970,150--Bailey and platinum-on-charcoal, platinum-on-gamma-alumina, platinum-on-silica gel, platinum-on-asbestos, and chloroplatinic acid,
(H.sub.2 PtCl.sub.6.6H.sub.2 O)
as mentioned in U.S. Pat. No. 2,823,218--Speier. Further, the platinum-containing material can be selected from those having the formula (PtCl 2 .olefin) 2 and H(PtCl 3 .olefin), as described in U.S. Pat. No. 3,159,601--Ashby. The olefin shown in the previous two formulas can be almost any type of olefin, but is preferably an alkene having from 2 to 8 carbon atoms, a cycloalkene having from 5 to 7 carbon atoms or styrene. Specific olefins utilizable in the above formulas are ethylene, propylene, the various isomers of butylene, octylene, cyclopentene, cyclohexene, cycloheptene, etc. A further platinum-containing material usable in the composition of the present invention is the platinum chloride cyclopropane complex (PtCl 2 .C 3 H 6 ) 2 described in U.S. Pat. No. 3,159,662--Ashby.
Still further, the platinum-containing material can be a complex formed from chloroplatinic acid with up to 2 moles per gram of platinum of a member selected from the class consisting of alcohols, ethers, aldehydes and mixtures of the above-described in U.S. Pat. No. 3,220,972--Lamoreaux.
Another compound to be used as a flame retardant additive is that disclosed in French Pat. No. 1,548,775 of Karstedt. Generally speaking, this type of platinum complex is formed by reacting chloroplatinic acid containing 4 molecules of water of hydration with tetramethyl-tetravinylcyclotetrasiloxane in the presence of sodium bicarbonate in an ethanol solution.
A large number of other platinum compounds, including complexes which are conventionally and generally widely known in the field of SiH-olefin addition reactions, are also useful in the practice of the present invention.
Small but effective amounts of platinum compounds are sufficient to impart flame retardancy to the silicone rubber. However, superior flame resistant compositions can be produced when the platinum is combined with the other flame retardant additives, as disclosed in this patent application. In general, amounts of from less than 1 to more than 250 parts per million as platinum based on the organopolysiloxane gum can be used. Preferably, the amount is from less than 1 p.p.m. to about 25 p.p.m. of platinum based on the organopolysiloxane gum. (When the gum is a methyl and phenyl-containing gum, it is preferable that less than 1 p.p.m. of platinum be used in order to prevent damage due to heat aging of the final product.)
For a further example of the kinds of silicone rubber compositions which will display improved flame resistance when practiced in conjunction with the present invention, see U.S. Pat. No. 3,660,345--Bobear, which is hereby incorporated by reference.
The platinum or platinum compound can be employed in amounts greater than 250 parts per million but due to the cost of the materials, utilization of greater than 250 p.p.m. is not preferred as the increased amounts do not provide significant improvement in the flame retardancy of the final material.
The platinum complex utilized in the examples below is a combination of approximately 4 parts chloroplatinic acid in a solution of approximately 70 parts methylvinyl tetramer and 20 parts ethanol and approximately 4 to 6 parts sodium bicarbonate.
EXAMPLE 1
A base compound was prepared as follows: 35.3 parts of devolatilized dimethylvinyl chain-stopped dimethyl methylvinyl polysiloxane gum having 0.05 mole percent methylvinyl siloxane units having a viscosity of approximately 25,000,000 cp at 25° C. was compounded with 36.4 parts of devolatilized trimethyl chain-stopped dimethyl polysiloxane gum having a viscosity of approximately, 25,000,000 cp at 25° C., 13.9 parts devolatilized dimethylvinyl chain-stopped dimethyl diphenyl methylvinyl gum having 0.05 mole percent methylvinyl siloxane units and 5.3 mole percent diphenyl siloxane units along the chain and viscosity of approximately, 55,000,000 cp at 25° C. and 9.9 parts of a devolatilized trimethyl chain-stopped dimethyl diphenyl polysiloxane having 5.3 mole percent diphenyl siloxane units along the chain and a viscosity of approximately, 55,000,000 cp at 25° C. To this was added 4.5 parts of a trimethyl chain-stopped dimethyl methylvinyl polysiloxane oil having 13.5 mole percent methylvinyl siloxane units and a viscosity of approximately 1,000,000 cp at 25° C. Additional ingredients desired to be included in a silicone rubber composition were 5 parts of cyclic dimethyl polysiloxane tetramer, 0.05 parts ferric octoate, and such process aids as 2.0 parts of low molecular weight trimethoxy chain-stopped dimethyl polysiloxane oil and 4 parts of low molecular weight silanol chain-stopped dimethyl polysiloxane oil. Additionally, 2.0 parts of hexamethyldisilazane filler treatment was utilized as well as 38 parts fume silica filler (Cabosil HS-5), and 12 parts extending filler (5μ Minusil). Also included in the base compound of this example 6 parts fume titanium dioxide. After compounding, this base mixture was heated to 160° to 170° C. for 1.5 hours under an N 2 atmosphere having a flow of 50 cubic feet per hour.
EXAMPLE 2
Several samples of the flame retardant silicone rubber of the present invention were prepared by compounding 100 parts of the base compound on a rubber mill with varying amount of the flame retardant additives.
Sample A contained 100 parts of the base compound of Example 1, 0.3 parts of the platinum complex described above and 1.5 parts of a curing agent in the form of a 50% solution of bis 2,4-dichloro benzoyl peroxide in silicone oil (Cadox TX-50).
Sample B was the same as Sample A but, additionally, contained 10 parts hydrated alumina.
Sample C was the same as Sample B but, additionally, contained 0.4 parts magnesum oxide.
Each of the Samples A, B, and C were formed into ASTM slabs and press cured for 10 minutes with 40 lbs. steam, whereupon the samples were post baked for 2 hours at 400° F.
The cured silicone rubber samples showed the following properties:
TABLE I______________________________________ Sample A B C______________________________________Shore A 56 57 59Tensile 1255 1100 1065Elongation 780 630 680Die B Tear 224 185 19860 Second Burn Test 10 28 0(Extinguishing, Time, Sec.)______________________________________
EXAMPLE 3
Another set of samples were prepared by starting with 100 parts of a base compound prepared by the method of Example 1. Table 2 demonstrates the effects of varying the amounts of hydrated alumina and magnesium oxide:
TABLE 2______________________________________ Sample D E F G H______________________________________Base Compound (parts) 100 100 100 100 100Platinum Complex 0.3 0.3 0.3 0.3 0.3Magnesium Oxide 0.4 0.4 0.4 0.2 0.6Hydrated Alumina 6 8 10 10 10Peroxide Catalyst 1.5 1.5 1.5 1.5 1.5Shore A 53 54 53 54 55Tensile (psi) 1110 1054 1000 990 985Elongation (%) 765 750 710 750 670Die B Tear (lbs./in.) 190 175 180 175 17060 Second Burn Test 21 5 0 0 0(Estinguishing Time, Sec.)______________________________________
EXAMPLE 4
Sample I was prepared in a manner analogous to Sample C above and therefore contained approximately 4 parts fume titanium dioxide per 100 parts of the base compound. Sample J was prepared in an analogous manner but without any fume titanium dioxide and the two samples compared as follows:
______________________________________ Sample I Sample J______________________________________Base Compound (parts) 100 100Platinum Complex 0.3 0.3Titanium Dioxide 4.0 --Hydrated Alumina 10 10Magnesium Oxide 0.4 0.4Peroxide Catalyst 1.75 1.75Shore A 54 55Tensile (psi) 1255 1280Elongation (%) 670 600Die B Tear lbs/in. 180 17560 Second Burn Test 0 0(Extinguishing Time, Sec.)______________________________________
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The present invention provides curable organopolysiloxane compositions having improved flame retardant properties, comprising, (1) an organopolysiloxane gum convertible to the cured, solid, elastic state and consisting essentially of silicon atoms, oxygen atoms and organic groups selected from the class consisting of methyl radicals, aromatic radicals selected from the class consisting of aryl and halogenated aryl radicals, vinyl radicals, lower alkyl radicals, lower cyanoalkyl radicals and lower haloalkyl radicals, (2) a finely divided inorganic filler, (3) a platinum compound or platinum and (4) and various effective amounts of hydrated alumina, fumed titanium dioxide, and magnesium oxide.
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FIELD OF THE INVENTION
The present invention relates to a method for regulating the supply of energy to a sealing device for the sealing of thermoplastic material with the object of achieving an optimum sealing result. The invention also relates to an arrangement for the realization of the method.
BACKGROUND OF THE INVENTION
In the welding together of plastic material it is important to adapt the supply of energy in such a manner that a tight and mechanically strong sealing joint is achieved. The sealing is accomplished in that two or more layers of plastic material are combined and are pressed together by means of a sealing element with simultaneous supply of heat or heat-generating energy, when the plastic material is caused to melt and its combined surface layers are fused together.
If the energy supplied is insufficient the tightness and strength are inadequate owing to the energy supplied not being capable of heating the plastic material to such a degree that a continuous fusing together of the layers pressed against each other is achieved. On the other hand, if the energy supply is excessive, burning of the material may occur, or else the material may be melted down to such a degree that it is removed from the location of the seal which consequently will be thinner and less strong.
In the sealing of laminated material comprising nonthermoplastic layers,such as e.g. laminate consisting of plasticcoated cardboard, the problem is not so pronounced as in the case where the material intended for sealing consists of pure plastic material or, in extreme cases, foamed plastic material.
In the sealing of expanded plastic materials, so-called foamed plastic material,which consists of a large amount of small cells with thin walls of plastic material,there is great need of the correct amount of energy being supplied to the sealing zone. The thin walls cannot be subjected to high pressure, since they would then be crushed together or "collapse". Such a collapse occurs too when they are exposed to excessive heat, since the thin cell walls will then melt down.
It has been known previously that sealing may be carried out by means of sealing elements which give off a certain defined amount of energy. This is done, for example, in the so-called "spin welding process", where the heat generated is in the form of frictional heat. "Spin welding" is carried out in such a manner that two pieces of plastic which are to be combined (usually two cup-shaped parts which are to be joined to a container) are rotated in relation to each other and that they are brought together while still rotating. The braking of the rotating parts, of which at least one is coupled to a flywheel with a certain inertia, generates frictional heat which is sufficient for joining the plastic parts to each other. By adjusting the speed of rotation etc. it is thus possible to determine accurately the energy which the rotating part has, and the whole of this kinetic energy is braked and is transformed to thermal energy when the plastic parts are brought together.
It is also known that with the help of electric contact breakers or regulators the length of the heat pulses can be adapted in such a manner that a certain defined energy is given off from a sealing element. In most cases these regulators are sufficient for adjusting the energy supplied, in particular when the contact pressure in each case of sealing is the same.
In certain cases, however, it is difficult to achieve conditions which given constant sealing pressure, e.g. in cases where the sealing objects are placed in a chain or a line of forming spaces connected to one other. It is difficult, for example, to make the forming spaces exactly like one another or to form the sealing objects in exactly the same manner. This may mean that the parts intended for sealing, when they are brought into sealing position and into contact with sealing elements, may receive different sealing pressure. It has been found that the sealing pressure has a strong influence on the energy supply, especially if the energy is supplied in the form of ultrasonics where high-frequency mechanical vibration produces heating of the material in a manner which partly resembles the earlier "spin welding process", that is to say the mechanical energy supplied is converted to frictional heat in the contact zone between the materials. Since the mechanical energy is not transmitted equally effectively when the contact pressure is low, a longer sealing time is required in such a case for the same energy to be generated in the sealing zone. In order to obtain the same sealing result and the same amount of energy supply it is necessary, therefore, to adjust the sealing time to the contact pressure, but since the packing containers intended for sealing, which arrive in a line after one another, are not exactly the same or placed in exactly the same way into their holders, the contact pressure may vary between packages following each other, so that there has to be an individual regulation in each sealing instance.
SUMMARY OF THE DISCLOSURE
The present invention provides directions in respect of a method and an arrangement for the realization of such a regulation, and the features characteristic for the invention are evident from the enclosed claims.
However, it has been found that this regulation too is not satisfactory in all field of application, and especially when foamed plastic material is laminated with a metal foil in order to increase its gas-tightness the sealing result may be different when diverse sealing times are used, even if the energy supply to the sealing element is exactly the same. The reason for this is that certain heat losses occur during the sealing operation and that these heat losses,broadly speaking,are proportional to the length of the sealing time. Thus the heat losses during a long sealing time will be greater than the heat losses in a shorter sealing period, which means that the energy available for the sealing will be less in the case of long sealing times, yet, as mentioned previously, long sealing times must be resorted to when the contact pressure between the sealing element and the sealing object is low.
The invention provides means, however, to overcome this problem too and to achieve an automatic compensation for long sealing times and, moreover, a compensation which can be varied, since the heat losses are not the same in the case of all packing material combinations.
BRIEF DESCRIPTION OF THE DRAWING
An embodiment of the invention will be described in the following with reference to the enclosed schematic drawing, wherein;
FIG. 1 is a schematic view of an arrangement for the manufacture of a packing container of foamed plastic material by welding.
FIG. 2 is a schematic view illustrating to illustrate the effect of the heat losses on the sealing result,
FIG. 3 is a schematic view of for an arrangement in accordance with the invention,
FIG. 4 is a time-voltage diagram showing how the capacitor in the integrating part of the coupling is charged.
FIG. 5 is a power-time diagram in respect of a sealing operation in accordance with the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The arrangement shown in FIG. 1 consists of a sealing element 1 where the sealing energy is supplied in the form of ultrasonic vibrations which through friction in the contact surfaces between the materials intended to be welded generate the heat which is required for sealing.
In the case shown, the sealing object consists of a line of coherent packing containers 3 which are formed in a chain 4 of coherent forming parts 2. In the case shown here, the packages 3 have been formed from two separate webs of foamed plastic material, one of which is formed into the coherent line of U-shaped parts in that the web is made to attach itself to the internal contours of the forming parts 2. Above this web of coherent U-shaped parts is arranged a second web whose central part covers the parts of the U-shaped spaces facing upwards while the edge zones of the second web are divided into lugs which are folded down and sealed against the lateral edges of the shaped parts. The coherent cavities so formed are filled with a liquid product which is supplied through a long and narrow filling pipe 5 situated above the raised fold of the first web which has been formed over the projecting walls of the forming parts 2 and the inside of the second web. After the filling operation the said first and second web would be joined to each other in a sealing joint, the raised lateral walls of the forming parts 2 serving as a holding-up tool in the sealing. As shown in the figure, the sealing element 1 has a pair of sealing jaws 6 consisting of ultrasonic vibrators which obtain their energy from an electrically fed vibration generator 7.
Even assuming it is endeavoured to make the forming parts 2 as identical as possible, it has been found that it is impossible to achieve the same sealing conditions for each link in the forming chain without the contact pressure between the sealing jaws 6 and the sealing zones being able to vary. As mentioned earlier, differences in the contact pressure between the sealing jaws 6 and the sealing object act in such a manner that the ultrasonics energy supplied to the sealing jaws will be different in different instances of sealing.
In accordance with the invention this phenomenon can be compensated by automatically prolonging the sealing times when the contact pressure is low and, consequently, the power of the sealing jaws is low. It is the aim, as mentioned previously, that the energy content in a sealing pulse should always be the same.
As is evident from FIG. 2, there are losses, though, during the sealing in the form of heat which is cooled away, so that not all the energy generated is utilized for the sealing. The heat losses, broadly speaking, are proportional to the length of the sealing period which means that the energy available for the sealing diminishes during long sealing periods and may diminish to such an extent that the sealing result becomes inadequate. This phenomenon is more pronounced in packing material containing an aluminium foil layer owing to the aluminium foil conducting the heat away more effectively from the sealing location. The abovementioned behavior is illustrated in FIG. 5 which shows a power-time diagram demonstrating the relationship between power and time for achieving a good sealing result.
In the case shown, the sealing pulses (I, II, III) have been approximated in such a manner that the power is constant during the whole pulse duration, that is to say the pulses are recorded in the diagram as rectangles. The area of the rectangles I, II, III is the same, which means that they represent the same energy content. The three sealing pulses shown have different sealing time, however and therefore different pulse output. The sealing pulse I, for example, represents the sealing time of the distance C--D and the power of the distance C--A. The corner point B of the sealing pulse thus represents a point on a curve 8, and on this curve all corresponding corner points for the rectangles representing sealing pulses will be situated even if the pulse duration varies as has been shown in FIG. 5. The curve 8 thus represents the relationship between required power and requried time for a certain sealing result to be achieved.
As mentioned previously, however, the heat losses increase with increasing sealing time and this too is illustrated in FIG. 5. It has been found that the heat losses are relatively constant and proportional to the sealing time, and in FIG. 5 the heat losses which are represented by hatched panels have been marked 10. It is evident from FIG. 5 that the heat losses during the short sealing pulse III are considerably less than the heat losses during the longer sealing pulse I. This means that the heat losses will reduce the energy of the sealing pulses to such an extent that an inferior sealing result is obtained unless compensation is made for the increased heat losses during a prolonged sealing period. In FIG. 5 the heat losses 10 too have been approximated as rectangles which agree relatively well and these heat losses have been added to, that is to say arranged above, their respective sealing pulses I, II, III. The energy which is conducted away through the packing material during the sealing pulse I is represented by the rectangle A--E--F--B and the energy supplied to the sealing generator thus has to be compensated to cover the losses by an energy which is equivalent to the hatched panel 10 being added to the sealing pulse I.
The corner point F of the rectangle C--E--F--D which represents the energy supplied from the sealing generator to the sealing element after compensation constitutes a point on a curve 9 which in FIG. 5 is shown as a broken line. This curve 9 will go right through the corresponding corner points on all compensated sealing pulses, and a comparison between the curves 8 and 9 makes evident that a varying sealing effect, which may be due for example to varying sealing pressure, cannot merely be adjusted by the length of the sealing period so as to make the energy-transmitting generator deliver a constant energy pulse, but it is also necessary to take into account that the losses increase with increasing sealing time.
To carry out the adjustment of the duration of the energy pulse which is necessitated by the effect of the sealing pulse given off being able to vary and to compensate for cooling during the sealing pulse an arrangement may be used of the type which is shown schematically in FIG. 3. As in FIG. 1, it is assumed that the sealing operat ion is to take place by means of ultrasonics, i.e. a generator 1 converts electric energy to mechanical vibrations which are transmitted to an ultrasonics horn 6 designed and mechanically tuned in a special manner, which can be pressed against the sealing object and thereby generates an internal friction between the objects intended for sealing, which are then heated up to such a degree that the thermoplastic layers facing each other fuse together to leak-tight and durable seal. The ultrasonics generator 1 is fed by a source of current 7 which produces an alternating current of a frequency and voltage suitable for the ultrasonics generator. The power delivered from the source of current depends upon the power which is drawn off by the ultrasonics horn 6 during the sealing operation. As mentioned earlier, this power transmitted will be less when the contact pressure is lower than when it is higher and this means that the current from the source of current 7 too will be less, since only so much current is drawn off as it takes to create the mechanical energy which is drawn off by the ultrasonics horn 6. The electric power is conducted from the source of current 7, which is constituted of an oscillator or high-frequency generator, through the leads 11 and 12 to the ultrasonics generator 1 wherein the electric energy is converted to mechanical vibrations. In the lead 12 is arranged a current transformer 13, by means of which is measured the current through the lead 12. Across the secondary winding of the current transformer 13 is arranged a resistor 14, and the voltage across this resistor constitutes a transformed value of the current through the lead 12. Between the feed wires 11 and 12 a voltage divider 15 is also provided which consists of high-ohmic resistors connected. The shown tap point on this voltage divider represents a transformed value of the voltage between the leads 11 and 12. Output voltages from the current transformer 13 and the voltage divider 15 are connected to the input terminals 16 and 17 of a so-called multiplier 18 wherein the voltages in the points 16 and 17 are multiplied with each other so as to provide a value of the electric power delivered by the high-frequency generator 7. The value of this power is represented as a voltage or potential 19 on the output of the multiplier 18. If for a moment the presence of the resistors 20 and 21 is disregarded, a current will flow through the capacitor C. The magnitude of this current depends upon the capacitance of the capacitor and the voltage across the capacitor, that is to say between the points a and b. For a more detailed explanation reference is made to FIG. 4 which shows a voltage-time diagram for the charging of the capacitor C. As is evident from the fully drawn line 22 a capacitor C will be charged according to a non-linear curve if the voltage across the charging circuit is constant and the capacitor will be successively charged with a diminishing current until the voltage across the capacitor corresponds to the charging voltage. Such a charging, therefore, will take place with varying charging current. In the case shown here, however, the charging of the capacitor C takes place with the help of a so-called operational amplifier F which is controlled by the voltage from the multiplier 18. The amplifier F endeavors to charge the capacitor C by means of a constant charging current and, that being so, a charging current which is proportional to the potential at the point 19 which, as mentioned earlier, represents a value of the electric power delivered from the source of current - generator 7. The coupling with the operational amplifier F and the capacitor C is often referred to as an integrator and the constant charging current is obtained because the amplifier controls the potential at the point b so that the voltage drop across the capacitor always remains such that a constant current flows through the same.
As mentioned before, the amplifier F is controlled by the potential from the multiplier 18. The charging current to the capacitor C is also delivered by the multiplier 18 and so as to limit the charging current a resistor 20 is connected between the multiplier 18 and the amplifier F. The voltage drop over the resistor 20 depends on the magnitude of the charging current and will affect the control of the amplifier F, but since the charging current is constant the voltage drop across the resistor 20 caused by the charging current will not vary.
In order to obtain a constant current through the capacitor C the potential at the point b thus has to be lowered continuously so that the curve 23 in FIG. 4 may become a straight line. In FIG. 4 is shown how the value U b is lowered with the charging time on charging of the capacitor according to curve 23. The point b is also connected, however, to a so-called comparator, that is to say, a device which compares two voltages and which, when the comparison shows that the voltages are the same, emits an output signal. The comparator K is connected via its terminal C to a lead 25 which is connected to a variable resistor 24, whose one endpoint is earthed and whose other endpoint is connected to a constant potential. The variable resistor 24 thus acts as a voltage divider making it possible by adjusting the position of the terminal 26 to vary the potential at the point c which, in the case shown here, obtains a negative potential since the resistor 24 is connected between earth potential and a negative potential. The set value of the potential in the point c is designated U b in FIG. 4 and is represented by a dash-dotted line. As mentioned previously, the potential in the point b will drop as the capacitor is charged, the potential in the point b being controlled by the amplifier F. When the potential in the point b, which is designated U b , attains the same value as the potential U b the comparator K senses that the two voltages are the same, which means that a recording pulse is emitted. This recording pulse controls a regulator R which breaks the energy supply to the generator 7 and thereafter acts upon the contact element S in such a manner that the contact is closed, which means that the capacitor C is discharged.
The sealed object now is removed from its sealing position and the sealing element 1 is made to engage with a new sealing object. and when this has taken place the generator 7 is reconnected to a source of current, the sealing element is activated and a new sealing pulse is generated.
In the manner as described above it is thus possible to obtain sealing pulses with constant energy content regardless of the effect of the sealing pulses, since a lower effect gives a lower output voltage 19 from the multiplier 18 which in turn means that the amplifier F is controlled in such a manner that the charging current through the capacitor C will become less and the charging time longer. In other words it takes longer for the potential in the point b to drop to the same value as the potential in the point c.
However, the circuit described does not provide any compensation for heat losses, but endeavors to deliver pulses from the electric feed generator with the same energy content irrespectively of the varying power output. It is possible, though, by a slight modification of the circuit to compensate for heat losses brought about by a prolonged sealing period. This may be done in that a variable leakage resistor 21 is inserted between the point a and a constant potential in the point d which in the present case is negative. Since there is a potential difference between the point 19 and the point d (the point 19 in general has a potential which is positive and is of a magnitude of one or more Volt) a current will pass straight through the resistor 20 and the resistor 21. This current has the effect that a voltage drop will arise across the resistor 20 which causes the potential in the point a to differ from, and be lower than, the potential in the point 19. This means that the regulator F will be controlled in such a manner that the charging current becomes smaller, and that as a result it will take a longer time to charge the capacitor C and to attain the voltage V c at the point b. In FIG. 4 a dash-dotted line 27 has been plotted which represents the compensated curve 23 and, as is evident from the curve 27, this curve crosses the value U c later than the curve 23. By adjusting the value on the resistor 21 the current through the resistor 20,and hence also the voltage drop across the resistor 20, can be varied so as to compensate for material with diverse thermal conductivity. Naturally the potential at the point 19 varies dependent on the power drawn from the source of current, but this voltage variation is small in relation to the voltage at the point d, so that it may be said, broadly speaking, that the compensation is independent of the power drawn off the generator 7.
In principle it may be said that the magnitude of the sealing pulse can be adjusted through appropriate setting of the potential at the point c with the help of the voltage divider 24 and that the compensation for heat losses is adjusted with the help of the variable resistor 21. The schematic arrangement described here functions well but it is possible, of course, within the scope of the concept of the invention to vary the appearance of the electric circuit in order to achieve the same result.
While this invention has been illustrated and described in accordance with a preferred embodiment, it is recognized that variations and changes may be made and equivalents employed herein without departing from the invention as set forth in the claims.
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A method for regulating the supply of energy to a sealing device for the sealing of thermoplastic material includes supplying electric energy to a sealing device pressed against the combined thermoplastic material with whose help the said electric energy is converted to thermal energy. The amount of energy supplied to the sealing device is variable to compensate for heat losses brought about by heat leakage during the sealing opertion. An arrangement for carrying out the method is also disclosed.
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CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C. §119(e) of pending U.S. provisional patent application Ser. No. 61/807,573, filed Apr. 2, 2013, and priority under 35 U.S.C. §119(a)-(d) of French patent application No. FR-13.52008, filed Mar. 6, 2013.
TECHNICAL FIELD
[0002] The present invention relates to a fluid dispenser device, such as a pump or a valve, for associating with a fluid reservoir so as to constitute a fluid dispenser. The dispenser device comprises: a body for mounting in stationary manner on the fluid reservoir; an actuator rod that is moved axially down and up inside the body; and a pusher that is mounted on the actuator rod by connection means. Advantageous fields of application of the present invention are the fields of perfumery, cosmetics, and pharmacy, in which it is common to use fluid dispensers for dispensing various fluids, such as perfumes, lotions, creams, gels, etc.
BACKGROUND OF THE INVENTION
[0003] When the pusher incorporates a fluid dispenser orifice, it is frequent for the actuator rod to define an internal fluid duct, and for the pusher to define an internal fluid channel that leads to a dispenser orifice, the connection means butt joining the duct to the channel in leaktight manner. In general, the pusher defines a connection sleeve that forms the inlet of the internal fluid channel. Conventionally, the connection sleeve is force-fitted around the free end of the actuator rod 23 , thereby forming a leaktight engagement.
[0004] In entirely conventional manner, the body and the actuator rod co-operate with each other to define a pump or valve chamber of volume that is variable. The inlet of the chamber is provided with an inlet valve and the outlet of the chamber is provided with an outlet valve. When the chamber is full of fluid, driving the actuator rod axially into the body causes the volume of the chamber to decrease and the fluid that it contains to be put under pressure. The inlet valve is forced into its closed state and the outlet valve opens under the effect of the pressure. The fluid may thus be discharged through the internal duct of the actuator rod and through the internal channel of the pusher for dispensing at the dispenser orifice. This design is entirely conventional for a pump or a valve in the fields of perfumery, cosmetics, and pharmacy.
[0005] In order to establish leaktight engagement between the pusher and the actuator rod, it is necessary to apply sufficient force on the pusher towards the actuator rod. This causes the actuator rod to be driven into the pump body, and causes a dose of fluid to be dispensed when the pump chamber is full of fluid. The operation of engaging the pusher on the actuator rod may thus cause fluid to leak between the actuator rod and the pusher, in particular when leaktight engagement has not yet been formed while fluid is being dispensed. In any event, leaktight engagement on the actuator rod requires the actuator rod to be driven in.
BRIEF SUMMARY OF THE INVENTION
[0006] An object of the present invention is to remedy the above-mentioned drawback of the prior art by defining connection means between the pusher and the actuator rod that do not require the actuator rod to be driven into the body while the pusher is being mounted on the actuator rod. Another object of the present invention is to use connection means that do not require any thrust on the actuator rod while the pusher is being mounted on the actuator rod. Still another object of the present invention is to achieve the above-mentioned objects without modifying the operation and the design of a conventional pump or valve.
[0007] In the prior art, US 2012/205401 is known for using the magnetization in order to connect a pusher on an actuating rod. Thus, the connection between the pusher and the actuating rod does not occur by pushing, but on the contrary by attraction, which obviates the depression of the actuating rod within the body. However, there is a problem with the tightness of the connection which has to be reached only by the magnetic attraction, and this is not easy. That is why the object of the present invention is to realize the tightness at the magnetic connection.
[0008] Thus, the present invention proposes a fluid dispenser device, such as a pump or a valve, for associating with a fluid reservoir so as to constitute a fluid dispenser, the dispenser device comprising: a body for mounting in stationary manner on the fluid reservoir; an actuator rod that is moved axially down and up inside the body; and a pusher that is mounted on the actuator rod by connection means including magnetizing means so as to generate a connection, by magnetic attraction, between the actuator rod and the pusher, the connection means comprising a rod organ engaged around the actuator rod and a pusher organ secured to the pusher, the actuator rod defining an internal fluid duct, and the pusher forming a connection sleeve defining an internal fluid channel that leads to a dispenser orifice, the dispenser device being characterized in that the rod organ is deformed by the connection sleeve of the pusher, thus joining the duct to the channel in leaktight manner. Thus, the deformation of the rod organ by the connection sleeve is used to realize the tightness. Advantageously, the magnetizing means comprise a magnet that is mounted on the pusher, and a ferromagnetic and/or magnetized element that is mounted on the rod organ.
[0009] According to an interesting feature of the invention, the rod organ is interposed between the duct and the channel so as to form a fluid product passage section. Advantageously, the rod organ includes a mounting collar that is engaged in leaktight manner on the actuator rod. Preferably, the actuator rod defines an annular upper edge, the mounting collar extending axially above this annular upper edge so as to form a fluid product passage section.
[0010] According to a first embodiment, the rod organ comprises a mounting collar supporting a gasket that is compressed by the connection sleeve of the pusher. Advantageously, the connection sleeve forms a projecting sealing bead that deforms the gasket locally. The mounting collar may support a ferromagnetic or magnetized cap. The ferromagnetic or magnetized cap advantageously holds the gasket on the mounting collar.
[0011] Thus, in this first embodiment, the mounting collar has only a support function for supporting a ferromagnetic or magnetized part that provides mechanical fastening in combination with the magnet of the pusher, and for supporting a gasket that provides sealing by compression by the connection sleeve of the pusher. The mechanical fastening, sealing, and support functions are clearly separate and distinct.
[0012] According to another feature, the rod organ comprises a mounting collar is provided with a flexible layer that comes into leaktight contact with the magnet that is mounted in the pusher. Advantageously, the flexible layer maintains the gasket on the mounting collar. In this way, the mechanical fastening by magnetization also serves to flatten the flexible layer so as to achieve sealing. In a variant, the mounting collar is made from a flexible material filled with ferromagnetic or magnetized particles. In this configuration, the mounting collar performs three functions, namely a support function, a function of mechanical fastening by magnetization, and a function of sealing by flexible deformation. Advantageously, the mounting collar includes a sealing rim that is flattened by the magnet of the pusher. Thus, the connection sleeve forms a first annular leaktight barrier, and the sealing rim that is flattened by the magnet forms a second concentric annular leaktight barrier.
[0013] The spirit of the invention resides in using magnetic attraction to form the leaktight connection between a pusher and an actuator rod, while avoiding pressing on the actuator rod or driving it into the body.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The invention is described more fully below with reference to the accompanying drawings, which show several embodiments of the invention by way of non-limiting example.
[0015] In the figures:
[0016] FIG. 1 is a vertical section view through a fluid dispenser in a first embodiment of the invention, with the pusher disconnected from the actuator rod;
[0017] FIG. 2 is a view similar to the view in FIG. 1 , with the pusher connected to the actuator rod;
[0018] FIG. 3 is a greatly enlarged view of the top portion of FIG. 2 ;
[0019] FIG. 4 is a view similar to the view in FIG. 3 , showing a second embodiment of the invention; and
[0020] FIG. 5 is a view similar to FIGS. 3 and 4 , showing a third embodiment of the invention.
DETAILED DESCRIPTION
[0021] Reference is made firstly to FIGS. 1 to 3 in order to describe in detail the first embodiment of the invention. The fluid dispenser device may be a pump or a valve: in the figures, it is a pump. The dispenser device is associated with a fluid reservoir R that includes a neck C. The reservoir R is not critical to the present invention and, as a result, it may present a wide range of configurations and may be made out of any appropriate material. It suffices that it is suitable for containing a fluid and for presenting an opening at a neck.
[0022] The fluid dispenser device of the invention comprises: a body 1 which, in this embodiment, is a pump body; an actuator rod 2 ; a pusher 3 ; and connection means 4 , 5 for connecting the pusher 3 to the actuator rod 2 .
[0023] In conventional manner, the pump body 1 includes a dip tube 11 that makes it possible to convey the fluid up to an inlet valve 12 that forms the inlet of a pump chamber 13 that is defined by the actuator rod 2 that includes a piston 21 and forms an outlet valve 22 . The pump body 1 also includes a projecting top collar 14 via which the body is held on the neck C of the reservoir R, e.g. by means of a fastener ring 15 that is associated with a neck gasket 16 . The fastener ring 15 may be of any kind, e.g. a crimping ring as in the figures, a screw-fastener ring, or a snap-fastener ring. The operation of the pump is entirely conventional: by driving the actuator rod 2 into the body 1 against a return spring, the volume of the chamber 13 decreases and puts the fluid that it contains under pressure. This causes the inlet valve 12 to be pressed into its closed position and the outlet valve 22 to be opened, such that the fluid under pressure can find a passage through the actuator rod 2 that forms an internal duct 23 . This design is entirely conventional for a pump in the fields of perfumery, cosmetics, and pharmacy. Optionally, a covering hoop 17 is engaged around the fastener ring 15 , the neck C, and the actuator rod 2 for reasons of appearance, or sometimes even functional reasons.
[0024] The pusher 3 includes a connection sleeve 31 having a bottom end that advantageously forms a projecting sealing bead 32 . The connection sleeve 31 internally defines an internal fluid channel 33 that leads to a dispenser orifice 34 , e.g. that may be formed by a nozzle for producing spray. This design is entirely conventional for a pusher that performs a dispensing function.
[0025] In the invention, the pusher 3 forms an annular housing 35 around the connection sleeve 31 . A magnet 5 , that is advantageously a permanent magnet, is received in the housing 35 . The magnet 5 may present a shape that is annular or cylindrical, in such a manner as to be engaged around the connection sleeve 35 . In a variant, the magnet 5 may be constituted by a plurality of magnet lugs that are distributed inside the housing 35 . Instead of the magnet 5 , it is also possible to provide a ferromagnetic element, e.g. an element based of iron, nickel, or cobalt. The magnet 5 or the ferromagnetic element constitutes a pusher organ forming part of the magnetizing means of the invention. The magnet 5 or the ferromagnetic element may be inserted directly into the housing 35 : in a variant, it may be mounted on a collar that is engaged in the housing 35 .
[0026] In addition, at its free end, the actuator rod 2 is provided with a rod organ 4 as connection means 4 for co-operating with the magnet 5 of the pusher 3 . In this first embodiment of the invention, the connection means 4 include a mounting collar 41 that is mounted by being engaged by force around the free end of the actuator rod 2 . By way of example, the mounting collar 41 may be made of plastics material. It serves as a support for a ferromagnetic element that is in the form of a ferromagnetic cap 43 that extends over at least the top of the collar 41 , and advantageously over its periphery in such a manner as to form a sheath. The ferromagnetic cap 43 may be held on the mounting collar 41 by being engaged by force. As a result of the ferromagnetic properties, the cap 43 is attracted by the magnet 5 of the pusher 3 that is arranged facing it. The magnet 5 may come into direct contact with the ferromagnetic cap 43 , as can be seen in FIGS. 2 and 3 . The magnetic attraction ensures that the pusher 3 is held on the actuator rod 2 with sufficient force. In other words, the magnetizing means constituted by the magnet 5 and the ferromagnetic cap 43 make it possible to fasten the pusher 3 mechanically on the actuator rod 2 .
[0027] The intimate contact between the bottom face of the magnet 5 and the ferromagnetic cap 43 could guarantee sealing at the connection between the internal duct 23 and the internal channel 33 . However, in the invention, provision is made to guarantee such sealing by providing an annular gasket 42 that is mounted on the mounting collar 41 and advantageously held in place by the ferromagnetic cap 43 . It should be observed that the annular top portion of the ferromagnetic cap 43 extends radially inwards onto the annular gasket 42 . The mounting collar 41 may be made with a recess that is suitable for receiving the annular gasket 42 in such a manner that its outer periphery is held by the ferromagnetic cap 43 .
[0028] Thus, when the pusher 3 is fitted on the connection means 4 , the magnet 5 bears against the ferromagnetic cap 43 , and simultaneously, the connection sleeve 31 comes into contact with the annular gasket 42 . The projecting sealing bead 32 deforms the annular gasket 42 locally so as to guarantee good sealing. In this way, the internal duct 23 is butt joined in completely leaktight manner to the internal duct 33 . Furthermore, the magnetic attraction generated by the magnet 5 and the cap 43 guarantees that the pusher 3 is fastened on the actuator rod in satisfactory manner, in particular during dispensing stages.
[0029] Reference is made below to FIG. 4 which shows a second embodiment of the invention. The fluid reservoir, the body 1 , and the actuator rod 2 may be strictly identical or similar to those of the first embodiment. The pusher 3 may also be identical or similar to that of the first embodiment: in particular it comprises a magnet 5 or a ferromagnetic element that is received directly or indirectly in the reception housing 35 formed around the connection sleeve 31 that preferably forms a projecting sealing bead 32 at its bottom end. In this second embodiment, the connection means include a rod organ 4 ′ forming a mounting collar 41 ′ that is engaged by force around the free end of the actuator rod 2 , as in the first embodiment. However, the mounting collar 41 ′ is made of a ferromagnetic or magnetized material. Thus, it performs two functions, namely both a support function and a function of mechanical fastening by magnetic attraction. The collar 41 ′ associated with the magnet 5 thus constitute magnetizing means. The mounting collar 41 ′ also supports an annular gasket 42 ′ for deforming by the connection sleeve 31 so as to form a leaktight butt joint between the internal duct 23 and the internal channel 33 . The mounting collar 41 ′ may come into direct contact with the magnet 5 . In a variant shown in FIG. 4 , the mounting collar 41 ′ is provided with a flexible layer 45 at its top face that is for coming into contact with the magnet 5 . In other words, the flexible layer 45 is interposed and flattened between the magnet 5 and the mounting collar 41 ′. The flexible layer 45 may be of any kind. By way of example, it may be made of an elastomer material. It makes it possible to form soft contact between the magnet 5 and the mounting collar 41 ′. Furthermore, as a result of it being flattened, it makes it possible to form a second leaktight barrier around the first barrier formed by flattening the annular gasket 42 ′. The flexible layer 45 may extend inwards onto the annular gasket 42 ′ so as to hold said annular gasket on the mounting collar 41 ′ in substantially similar manner to the first embodiment. The inner edge of the flexible layer 45 may even come into leaktight contact with the connection sleeve 31 so as to provide additional sealing. In a variant, the flexible layer 45 may be secured to the magnet 5 and not to the mounting collar 41 ′. Although not shown, it is also possible to eliminate the annular gasket 42 ′ and to form direct contact between the connection sleeve 31 and the top end of the actuator rod 2 , with sealing being guaranteed entirely by the flexible layer 45 .
[0030] With reference to FIG. 5 , a third embodiment of the invention can be seen in which the body 1 , the actuator rod 2 , and the pusher 3 may be identical or similar to those of the first and second embodiments. Only the connection means 4 ″ differ from the first and second embodiments. In fact, these connection means comprise a rod organ 4 ″ only constituted by a mounting collar 41 ″ that is engaged by force around the free end of the actuator rod 2 . The mounting collar 41 ″ is made of a flexible material, such as an elastomer, that is filled with ferromagnetic or magnetic particles 46 that are embedded in the mass of the mounting collar 41 ″. Thus, the mounting collar 41 ″ performs three functions, namely a support function, a function of mechanical fastening by magnetization, and a function of sealing by deformation. The magnet 5 of the pusher 3 may come into direct contact with the mounting collar 41 ″ that is advantageously provided with one or more toroidal rings 47 that project from the top face of the mounting collar 41 ″. The toroidal rings 47 are deformed a little by the magnet 5 in such a manner as to create one or more leaktight annular barriers. In addition, the bottom end of the connection sleeve 31 , that optionally is provided with a projecting sealing bead 32 , also comes into contact with the mounting collar 41 ″ so as to deform it and thus create a leaktight barrier. Without going beyond the ambit of the invention, it is possible to eliminate the annular rings 47 or the projecting bead 32 . Provision can also be made for the connection sleeve 31 to come into direct contact with the top end of the actuator rod 2 .
[0031] In very general manner, the invention makes it possible to connect the pusher mechanically on the actuator rod by using magnetizing means. The pusher may be a simple pusher without dispenser outlet, such that mechanical fastening is sufficient. When the pusher incorporates a dispenser orifice and an internal channel, mechanical fastening by magnetic attraction must also guarantee sealing at the butt joint between the internal duct 23 of the actuator rod and the internal channel 33 of the pusher. In every embodiment, it is to be noted that the rod organ, and more particularly the mounting collar, is interposed between the duct 23 and the channel 33 so as to form a fluid product passage section. The mounting collar is advantageously engaged in a leaktight manner around the actuator rod 2 and individually or cumulatively performs a support function, a fastening function, a sealing function and/or a fluid product passage function.
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The invention relates to a fluid dispenser device, comprising: a body for mounting in stationary manner on the fluid reservoir; an actuator rod that is moved axially down and up inside the body; and a pusher that is mounted on the actuator rod by connection means including magnetizing means so as to generate a connection, by magnetic attraction, between the actuator rod and the pusher. The connection means comprises a rod organ engaged around the actuator rod and a pusher organ secured to the pusher, the actuator rod defining an internal fluid duct. The pusher forming a connection sleeve defining an internal fluid channel that leads to a dispenser orifice. The rod organ is deformed by the connection sleeve of the pusher, thus joining the duct to the channel in leaktight manner.
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BACKGROUND
The present invention relates to flat panel display and semiconductor manufacturing equipment, and particularly to a hot plate oven and a method for baking materials on substrates such as flat panel displays and semiconductor wafers.
Flat panel displays and wafers are baked by placing them in a hot plate oven. Typically, the hot plate oven includes a heated chuck that has a set of three to four proximity pins protruding from the heated chuck to hold the substrate above the heated chuck. Some hot plate ovens have large top doors that expose the substrate to considerable ambient air when the substrate is placed in the oven. In a typical oven used to bake substrates, the thermal environment will be greatly disturbed when the large top door is opened. Thus, after introduction of the substrate in the oven there will be undesirable lag time to achieve thermal equilibrium which slows production. Further, when the large top door opens contamination in the ambient air may be introduced. In addition, when hot plate ovens having large top doors are stacked upon each other they will need large vertical clearance space between each oven to permit placing the wafers through the top of the oven, which in turn leads to a need for large vertical robot travel requirements which raises the total cost of the processing equipment.
Hot plate ovens have used a set of three to four lift pins to lift the substrate off the heater surface to enable robotic handling systems to transfer substrates in and out of the oven. The lift pins do not, however, fully support the substrate in the center which then sags due to substrate's own weight and a high oven temperature. This is a particularly difficult problem for flat panel displays and large size wafers such as 300 mm diameter silicon wafers and for substrates having a high coefficient of thermal expansion. Further, the lift pins become hot in the oven over time and tend to leave an image on the top of the substrate opposite the contact point of the lift pin on the bottom of the substrate due to the volatility of the solvents used in some of the chemicals (e.g., blue color filter material and polyimides) contained in the coating material. Beyond any appearance related concerns the images indicate the physical characteristic of the substrate have changed in some indeterminate way at and about the image which makes the substrate unacceptable for further processing.
SUMMARY OF THE INVENTION
The present invention provides an oven and a method for baking materials on substrates. In one embodiment, the oven includes an insulated chamber, a heater in the chamber, a door for entry of a substrate, a frame, preferably water cooled, for suspending the substrate above the heater, a substrate lowering mechanism to hold the frame and lower the substrate to a certain height above the heater, and a set of manifolds and valves to feed and exhaust gases, vapors, and apply a vacuum to the chamber. A temperature control system controls the set point temperature of the heater and cuts off power to the heater to protect the heater if the heater temperature goes beyond a certain limit.
In another feature of the invention, the oven assembly includes a stack of low profile ovens, each having a door on the side for entry of a substrate. Much less vertical space is needed between the stacked ovens because the wafers enter the chambers through the side doors rather than through top of the ovens. This feature of the invention reduces the amount of vertical travel needed by the robot transporting substrates in and out of the oven. Because the oven chamber is preferably sealed and the door opening is minimized and conforms to the substrate geometry, the oven environment, thermally and chemically, can be easily and closely controlled during introduction of the substrates, and better process results are obtained.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an isometric view of the assembled hot plate oven, including a door in the open position for insertion of a substrate into the oven chamber by a wafer handler such as a robotic arm end effector.
FIG. 2A is a bottom view of the heater block illustrating the layout of the heating elements with terminations and the central pin.
FIG. 2B is a side view of the heater block illustrating the terminations of the heating elements and the central pin with its cooling tubes.
FIG. 3A is a top view of the hot plate oven illustrating the door assembly and the display holding frame.
FIG. 3B is a side view of the hot plate oven illustrating the door assembly, the substrate raising plate, the display holding frame, the heater block, and the chamber housing.
FIG. 4A is a front view of the hot plate oven with the door assembly removed. A partial cutaway on the left of the drawing illustrates the arrangement of the heater block, the central pin, the display holding frame with a substrate on the frame, the insulation, the housing cover, the spacer rod, and the substrate raising plate.
FIG. 4B is an enlarged partial cutaway of the left hand side of the front of the oven with the door assembly removed. It illustrates the arrangement of the heater block with its underlying support, the frame, the insulation, the housing cover, the spacer rod, the sealing plate and the substrate raising plate.
FIG. 5 illustrates an isolated view of the door assembly with the door in the open position.
FIG. 6 illustrates the display holding frame by itself for holding a substrate.
FIG. 7 is an isometric view of the fluid cooled central pin with its associated cooling tubes.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following description includes the best mode of carrying out the invention. This detailed description is made for the purpose of illustrating the general principles of the invention and should not be taken in a limiting sense. The scope of the invention is best determined by reference to the claims.
The invention provides a hot plate oven and a method suitable to bake materials on substrates such as flat panel displays and large semiconductor wafers such as 300 mm in diameter and above. In a typical application, baking is done in a hot plate oven after coating the substrate with chemicals such as photoresist (resist) to dry out any solvents and form one or more uniform layers of the material on the top of the substrate.
In an another application, the hot plate oven can be used in conjunction with a vapor prime process such as those used in the semiconductor industry. For instance, one vapor prime process might use a priming agent such as hexamethyldisilane (HMDS) maintained in a liquid phase in a canister. When HMDS is added into the oven chamber, nitrogen gas at 5 psig or less is bubbled through the liquid HMDS, and the saturated vapor introduced into the oven chamber for less than a few minutes under a vacuum such as 15 inches of Hg. Introduction of the saturated vapor of nitrogen and HMDS is then stopped and pure nitrogen is supplied to purge the oven chamber while the chamber is exhausted. The vapor prime process is believed to provide better adhesion properties between the substrate and resists. During the vapor prime process the oven is maintained at about 150-180 degrees C.
FIG. 1 is an isometric view of the assembled hot plate oven 70. The hot plate oven 70 includes a door 40, shown in the open position, for entry of a wafer handler such as robotic arm end effector 67 to bring a substrate 69 into a oven chamber defined by a chamber housing 48 and housing cover 52 where the material on substrate 69 is baked. The door 40 is opened and closed by movement of piston rods 72 and 73 within cylinders 35 and 44 (FIG. 3A), respectively. As shown in FIG. 1, the hot plate oven 70 includes a heater block 1 in the chamber housing 48 providing heat to the substrate 69. A substrate raising plate 50 can be raised and lowered vertically upon demand by cylinders 55 and 49 (FIG. 3A) which in turn raise and lower a display holding frame 29 (FIG. 3B) which suspends the substrate 69 in the chamber housing 48 above the heater block 1 and below the housing cover 52. Two manifolds 63 and 64 are in fluid communication with the chamber housing 48 through the back of the oven 70 and supply and/or exhaust gas to the chamber housing 48, or even pull a vacuum from the chamber housing 48 depending on the given process requirements.
FIG. 2A is a bottom view of the hot plate oven with emphasis on the heater block and layout of the heating elements with their terminations and a central pin. As shown in FIG. 2A, the heater block 1 includes a first heating element 74, a second heating element 76, and a third heating element 78 which are resistive heating elements which make contact with the heater block 1 and are disposed in a snake like pattern. The heater block 1 can be made of a suitable conductor such as aluminum. The first heating element 74 includes terminations 6 and 7, the second heating element 76 includes terminations 9 and 10, and the third heating element 78 terminations 5 and 8. A first power supply wire 2 connects to termination 10 of the second heating element 74 and termination 6 of the third heating element 78. A second power supply wire 3 connects to termination 5 of the third heating element 78 and termination 6 of the first heating element 74. A third power supply wire 4 connects to termination 6 and 7 of the first heating element 74. Power is supplied to the power supply wires 2, 3, and 4 from 208 V three phase AC source. The heating elements 74, 76, and 78 and the wires 2, 3, and 4 are insulated where they are exposed and non-insulated in the heater block 1. A central pin 11 is disposed in a central region of the heater block 1 and is held in place by screws into the heater block 1. In an alternative embodiment, the central pin 11 may include more than one central pin, and need not be restricted to being disposed at the center of the heater block 1. The central pin 11 only needs to be disposed in the heater block 1 so as to function to counteract any sag of the substrate 69 during the baking process.
FIG. 2B is a side view of the heater block 1 illustrating the terminations 5, 6, 7, and 8 of the heating elements and the central pin 11 with its cooling tubes 14 and 15. Termination 8 includes a heating element 78 (FIG. 2A) which ends in a threaded post 80. Nuts 82 and 83 secure the power supply wire lug 84 to the heating element 78. The other terminations 5, 6, and 7 shown in FIG. 2B and terminations 9 and 10 shown in FIG. 2A are of similar construction to termination 8, and lie parallel to the plane of the heater block 1. As a result, the hot plate oven 70 is a low profile oven capable of being stacked in a multiple oven assembly.
A cooling fluid such as water is supplied to the cooling tubes 14 and 15 of the central pin 11 to carry heat from the central pin 11 to maintain the central pin 11 at a lower temperature than the heater block 1. The central pin 11 prevents sagging in the center of the substrate 69 (e.g., flat panel display and the larger wafers) due to thermal expansion during the baking process, prevents an image from appearing on the top of the substrate 69 opposite the contact point of the pin 11, and protects the integrity of the physical characteristics of the coated substrate 69.
FIG. 3A is a top view of the hot plate oven 70 illustrating the door assembly and the display holding frame 29. To illustrate these features the hot plate oven 70 is shown without the housing cover 52 (FIG. 3B) in place, without the substrate raising plate 50 (FIG. 3B), and with the door 40 in the open position. The door assembly includes a door 40 of preferably aluminum having a door seal 39 preferably of a silicone O-ring. The door 40 is attached to a shaft 41 held in place by bearings 38 and 68 on the ends of the shaft 41. The shaft 41 is connected to lever 37 and lever 42 at each of its ends, which are connected to clevis 36 and 43 which are at the end of the piston rods 72 and 73. The piston rods 72 and 73 slide within cylinder 35 and 44 which are mounted at pivots 34 (FIG. 3B) and pivot 45 (FIG. 5) to brackets 33 and 46 extending to chamber housing 48 (FIG. 3B). As a result, the hot plate oven 70 is a low profile oven capable of being stacked in a multiple oven assembly. The display holding frame 29 with its associated spacer rods 28, 30, and 32, the cylinders 49 and 55 along with the piston rods 115 and 116 and the central pin 11 in the heater block 1 (FIG. 3B) are shown which actuate the raising and lowering of the display holding frame within the hot plate oven. The manifolds 63 and 64 extending from the backside of the chamber housing 48 are also shown.
FIG. 3B is a side view of the hot plate oven 70 illustrating the door assembly, the substrate raising plate 50, the display holding frame 29, the heater block 1, and the chamber housing 48. To illustrate these features the hot plate oven 70 is shown with the housing cover 52 and substrate raising plate 50 in place and with the door 40 in the open position. The details of the door assembly and the manifold 63 are discussed above in connection with FIG. 3A. FIG. 3B is a partial cutaway at the back of the chamber housing 48 to illustrate the arrangement of the heater support 56, the heater block 1, the display holding frame 29 above the heater block 1, the insulation 62 lining the chamber housing 48, the housing cover 52, the spacer rod 30, and the substrate raising plate 50. As shown in FIG. 3B, the display holding frame 29 is attached to spacer rods 28, 30, and 32 which are attached at the other end to the substrate raising plate 50. The spacer rods 28, 30, and 32 enter the housing chamber through the seal plates 51, 53, and 54 as shown in FIG. 4A. The display holding frame 29 moves up and down when the piston rods 115 and 116 move vertically in their cylinders 49 and 55 as shown in FIG. 3A. The resistance temperature devices 65 and 66 enter the housing chamber 48 through the backside of the hot plate oven 70 and monitor the temperature in the heater block 1.
FIG. 4A is a front view of the hot plate oven 70 with the door assembly removed. A partial cutaway on the left of the drawing illustrates the arrangement of the heater block 1, the central pin 11, the display holding frame 29 with a substrate 69 on the display holding frame 29, housing cover 52, the spacer rods 28, 30, and 32, the seal plates 51, 53, and 54, and a substrate raising plate 50. The display holding frame 29 includes a stiffener plate 29 which is attached with screws 25 and 27.
FIG. 4B is an enlarged partial cutaway of the left hand side of the front of the hot plate oven 70 with the door assembly removed. All the parts are as described earlier in connection with FIG. 3B. FIG. 4B shows the overlapping joints 58 of the insulation 57, 59, and 62, and the relationship between the seal 61 within the seal plate 51. One material suitable for the insulation is any ceramic insulation used in hot plate ovens capable of withstanding damage under high temperatures such as 250 degrees Centigrade.
FIG. 5 illustrates the door assembly with the door in the open position. FIG. 5 shows the isometric view of the oven door and its operating mechanism alone. The components of the door assembly were described earlier in connection with FIG. 3A, and can be made of aluminum with the exception of the shaft 41 and the piston rods 72 and 73 which are preferably made of 300 series stainless steel.
FIG. 6 illustrates the display holding frame 29 of preferably a series 300 stainless steel by itself for clarity. During the baking operation, the substrate 69 is supported on its edges by the projections 23 extending along the bottom side of the display holding frame 29. The spacer rods 28, 30 and 32 are press-fit into the display holding frame 29. A cooling tube 31 also of preferably stainless steel is attached by welding to the display holding frame 29 to provide water or nitrogen cooling for the display holding frame 29. The stiffener plate 22 connects the two front sides of the frame 29 by means of the screws 24-27 and 18-21, and has adequate clearance to allow the robotic end effector 67 (FIG. 1) to place the substrate 69 on the frame 29.
FIG. 7 is an isometric view of the fluid cooled central pin 11. The central pin 11 has machined in holes for passage of cooling fluid so that the fluid enters travels in a circuit from the bottom to top of the central pin 11 and back to cool the tip of the central pin 11. In one embodiment, the central pin 11 can be water or nitrogen cooled to maintain the tip of the central pin 11 at around the room temperature. Thus, thermal shock can be reduced to a minimum when the substrate 69 comes in contact with the central pin 11. The cooling fluid enters first through the cooling tube 14, then the fitting 13, then the cooling tube 17, then into the central pin 11, then the tube 17, then the fitting 16, and finally through the tube 15. The fluid flow rate and type of fluid can be obviously adjusted to accommodate the process temperature requirements.
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The invention provides a hot plate oven and a method suitable to bake materials on substrates such as flat panel displays and large semiconductor wafers such as 300 mm in diameter and above. The hot plate oven in one embodiment includes an insulated chamber, a heater in the chamber, a door for entry of a substrate, a frame, preferably water cooled, for suspending the substrate above the heater, a substrate lowering mechanism to hold the frame and lower the substrate to a certain height above the heater, and a set of manifolds and valves to feed and exhaust gases, vapors, and apply a vacuum to the chamber. In another feature, the oven assembly includes a stack of low profile ovens, each having a door on the side for entry of a substrate.
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[0001] This is a continuation of application Ser. No. 08/087,178 filed Jul. 2, 1993, which is a continuation-in-part of application Ser. No. 07/960,085 filed Oct. 9, 1992.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of germicidal systems employing bacteria-destroying ultraviolet lights. In particular, the present invention relates to a system for producing an air flow through a baffled ultraviolet sterilization chamber mounted behind a wall or ceiling, wherein the ultraviolet light intensity, the air residency time, and the air exchange rate for the air volume in a given space, are such that a percentage of tuberculosis bacteria are destroyed that effectively prevents transmission of such disease by airborne sputum.
BACKGROUND OF THE INVENTION
[0003] Tuberculosis is the most common cause of death from infectious disease in the world today. It infects millions of people each year and causes hundreds of thousands of fatalities. The disease is particularly prevalent in less-industrialized countries where high population densities, poor sanitary conditions and a high percentage of individuals in poor health contribute to the spread of infectious diseases.
[0004] After a long period of declining rates of tuberculosis infection in the United Sates, it is believed that the infection rate is now increasing. The increasing rate is apparently due to a combination of factors. One factor is undoubtedly increased immigration from parts of the world with high rates of infection. For example, in the United States the case rate of tuberculosis per 100,000 population was 9.3 in 1985, resulting in over 22,000 cases and over 1,200 deaths. In Southeast Asia, both the case rate and the death rate are believed to be many times that, and immigrants from that part of the world now constitute 3 to 5% of new cases in the United States.
[0005] Another factor related to increased rates of tuberculosis infection appears to be the use of living quarters with high population densities and less-than-ideal sanitary conditions for persons in ill health who are susceptible to the disease. Such conditions are commonly found in shelters for the homeless, prisons and some nursing homes. Another important factor in the increased rate of infection is infections among patients with Acquired Immune Deficiency Syndrome (AIDS) and intravenous drug users.
[0006] Another reason for the recent increased incidence of tuberculosis is probably the failure of many medical professionals to diagnose and treat the disease early and properly. The relative rareness of the disease in the United States since the early epidemics resulted in an entire generation of health care workers without much experience in the disease. Further, diagnosing the disease is not always easy, for the symptoms are similar to the symptoms of many other disorders. Therefore, the disease is often misdiagnosed and mistreated, and the degree of infectiousness of the disease is underappreciated.
[0007] Even after it is recognized that a set of symptoms may indicate tuberculosis, the tests for the disease are somewhat imprecise and tend to require judgment by an experienced professional. For example, one diagnostic tool is chest x-rays which typically show apical-posterior segment cavitary changes in tuberculosis infected patients. However, in elderly individuals—who comprise a relatively large proportion of tuberculosis patients—lobar or patchy lower-zone shadows may simulate bacterial or aspiration pneumonia. Also, x-rays in the elderly may mislead the physician by showing a solitary pulmonary nodule or a pleural effusion. Another important tuberculosis test is the tuberculosis skin test, but a major disadvantage to the tuberculosis skin test is that it generates a high number of both false-positive and false-negative results. The most precise test is microscopic examination of a sputum sample, but this test may require the use of at least three separate samples of sufficient volume, which may require gastric aspiration or bronchoscopy in patients with low sputum production.
[0008] The normal body reaction to infection by tuberculosis bacteria is to build a fibrous wall around each bacterium. Initially, a person may be unaware of any infection, but over a period of months or even years the infection produces inflammation and eventually destruction of tissue. The manifestations as the disease progresses generally include cough, fever, night sweats, hemoptysis, chest pain, weight loss and malaise. The usual treatment for tuberculosis is administration of drugs over a period of many months such as isoniazid, rifampin and pyrazinamide and ethambutol. Persons recently infected but with no active disease are usually given isoniazid preventive therapy, particularly if they have other risks such as malnutrition, gastrectomy, diabetes mellitus, pneumoconiosis, malignancy or if for some reason they have immunosuppression such as from corticosteroid therapy, renal impairment or HIV infection. In short, tuberculosis in a normal healthy patient is typically a disease that is curable by drugs, although the drug therapy is quite prolonged. A serious concern—and yet another reason for the recent increase in tuberculosis—is the development of drug-resistant tuberculosis. It is estimated that at least 5% of new cases are resistant to the usual drug therapy, and that the percentage in some areas of the United States is as high as 20%. While non-drug-resistant tuberculosis is typically 99% curable in patients with normal immune responses, drug-resistant tuberculosis is only about 50-60% curable. A related concern is drug therapy on nondrug-resistant tuberculosis for patients who are intolerant of the drugs. In those cases, drug therapy is complicated because the drug is effective against the infection but has serious adverse effects on the patient such as hepatitis or serious rashes.
[0009] Another concern is raised by the increasing incidence of non-tuberculosis mycobacterial pulmonary infections. Many such infections produce symptoms similar to those of tuberculosis infections, but may be more difficult to identify and treat. Moreover, they may be transmitted through the same means as tuberculosis and tend to infect the same types of susceptible individuals.
[0010] The transmission of the tuberculosis bacteria is accomplished almost exclusively by infected individuals expectorating microdroplets of bacteria-containing sputum by coughing or sneezing. These microdroplets are suspended in the air and are inhaled by other individuals in the vicinity. The bacteria typically lodges in the lower lung where it proliferates, and may be disseminated to other organs as well. The microdroplets of sputum which contain the bacteria may be very small—on the order of 0.01 microns. In fact, it appears that the smallest droplets are the most effective in communicating the disease since the smallest droplets stay airborne indefinitely and are easily inhaled to the lower lung where they are not readily removed. Studies have shown that aerosol droplets on the order of 1-5 microns are highly effective vehicles for transmitting the disease.
[0011] One controversial approach to combatting the disease has been the use of vaccines. However, the efficacy of tuberculosis vaccines is debatable. Even the trials which seemed to show some efficacy have shown less efficacy among adults than among infants and children. An additional objection to widespread vaccinations is that by inducing tuberculin reactivity in the population they would confound the detection and measurement of infections through the use of skin tests, since skin tests in vaccinated individuals would presumably result in a false-positive. This would severely curtail the practice of preventive drug therapy among infected patients who have not yet developed outward symptoms.
[0012] The airborne aspect of the disease has led toward systems for preventing the transmission of the disease which focus on filtration and sterilizing devices. One approach is the use of masks. Simple surgical masks are thought to be insufficient in view of the very small size of the sputum microdroplets which are effective in communicating the bacteria. Instead, disposable particulate respirators are recommended. The use of masks is fraught with practical difficulties; they are physically uncomfortable, they impair breathing (which is already impaired for many patients), and they disrupt speaking. To be effective at all, it would probably be necessary for the masks to be worn not just by the patients, but also by noninfected individuals. In view of the long distances that airborne microdroplets containing viable bacteria can travel, it would be necessary for the masks to be worn by noninfected individuals throughout the general vicinity of a patient and not just those in the immediate presence of a patient. Moreover, it is not known for certain whether the use of masks would actually be effective even if the practical problems were tolerated or overcome.
[0013] Another preventive measure which relies on the airborne aspect of the bacteria is the use of modified ventilation systems. It is currently recommended that facilities used for tuberculosis patients undergo certain minimum air exchange rates, under the theory that dilution of infectious air with clean air will reduce the concentration of bacteria and hence the likelihood of transmission of the disease. While this approach is theoretically sound, it is problematic in implementation. Modern buildings are normally designed with fixed ventilation systems which are not easily modified to produce the requisite air exchange rate. Even if they are suitably modified, they may be rendered ineffective by an open door or by shifting air-flow patterns. A high air exchange rate also increases cooling and heating costs. Finally, there is the issue of the ultimate disposition of the contaminated air that is removed, and whether it is appropriate to simply release it outside the facility.
[0014] Another approach to reducing the transmission of the disease is the use of high-efficiency filtration systems. For such a system to be effective, however, it must employ a very dense filter to trap very small particles. This entails a powerful lan, high energy usage, loud noise, and meticulous installation and maintenance. There is also concern that the filters and the rest of the air-flow path may themselves become sites of bacteria colonization.
[0015] Yet another approach to reducing the transmission of the tuberculosis bacterial employs ultraviolet light as a germicide. It was discovered some time ago that airborne bacteria are susceptible to ultraviolet light in wavelengths of about 254 nm. Wells S. F., On Air - Borne Infection: II - Droplets and Droplet Nuclei, Am. J. Hyg. 1934 20: 611-8; Wells W. F., Fair G. M., Viability of E. Coli Exposed to Ultraviolet Radiation in Air, Science 1935; 82:280-1. That finding led to the development of systems using ultraviolet light as a germicide against airborne bacteria such as measles and tuberculosis. However, interest in such systems diminished when later investigators were unable to obtain the desired efficacy. Also contributing to the diminished interest in such systems was the recognition that ultraviolet lights produced harmful ozone and also produced skin and eye irritation. With the development of streptomycin and chemotherapy for tuberculosis treatment, the belief became prevalent that tuberculosis would be eradicated and that preventive systems would be unnecessary.
[0016] The systems that were developed using ultraviolet light as a germicide against tuberculosis were imprecise, marginally effective, and perhaps dangerous. The most common system simply employed ultraviolet lights mounted on or suspended from a wall or ceiling of a room. For example, a system employing lights suspended from the ceiling is described in some detail in Riley, R. Z., Knight, M. and Middlebrook, G., Ultraviolet Susceptibility of BCG and Virulor Tubercle Bacilli, Am. Rev. of Resp. Dis., 1976, 113:413. The problems in such a system are numerous. It relies completely on normal air circulation in the room where it is installed to bring the bacteria within range of the ultraviolet light. The normal circulation in a room may be too low for the ultraviolet light to destroy a necessary proportion of bacteria, or the normal circulation may be high enough but of a pattern that does not bring the airflow past the ultraviolet light. Moreover, there is no single test to determine whether the circulation rate and patterns are adequate or not for a given installation. Further, such systems quickly become contaminated by dust on the light bulbs which diminishes their effectiveness. From a safety standpoint, one of the greatest concerns is that the simple light shields used with such systems allow light to be reflected off the walls and ceiling and onto the skin and eyes of the occupants. The degree of danger associated with the indirect ultraviolet irradiation is disputed, but there is undoubtedly at least some danger if the period of exposure is prolonged. In explaining the necessary safety precautions, Riley, R. L. and Nordell, E. A., Clearing the Air, The Theory and Application of Ultraviolet Air Disinfection, Am. Rev. Respir. Dis. 1989 139:1286, stated:
[0017] Does germicide UV cause inflammation of skin and eyes? It can, but the standard set by the National Institute of Occupational Safety and Health (NIOSH) is very conservative. Overhead installations must be inspected for ‘hot spots’ (greater than 0.2 uW/cm 2 ) with a sensitive UV meter. Installers should anticipate readjusting fixture height up or down based on meter readings. Baffles designed to prevent direct eye contact will also need adjustment after the initial installation. Excessively reflective surfaces about fixtures may contribute to excess radiation, but this can be reduced with nonreflective paint or by spraying the surface with stove black. If the intensity of UV does not exceed 0.2 uW/cm 2 , the likelihood of skin or eye irritation is minimal during an 8-h exposure. Persons with especially sensitive skin, with systemic lupus erythematous, for example, may need to avoid exposure or take measures to protect their skin.
[0018] This illustrates some of the difficulties and dangers of employing ultraviolet lights behind a simple light shield; the light may generate dangerous and unpredictable “hot spots”, it is not appropriate for those with sensitive skin or eyes, and it requires careful consideration of the placement and the orientation and reflectivity of the surrounding surfaces. Finally, even if all those precautions are observed, the quote only indicates that skin and eye irritation is “minimal” rather than nonexistent and only for exposure periods of 8 hours. Of course, for the system to be effective against transmission of airborne disease in, for example, a patient room, it would have to operate continuously and not just for 8 hour periods. The article goes on to acknowledge that:
[0019] UV or disinfection that is inappropriately applied, poorly planned, or carelessly used may be ineffective, dangerous, and falsely reassuring. The guidelines and precautions listed above are not intended to enable a would-be user of UV to plan, purchase, install, or check the adequacy of a UV installation. Detailed instructions for UV installers have been published. However, there is currently little commercial interest in UV for air disinfection and, therefore, little expert guidance for comprehensive planning and installation. Renewed consumer interest may stimulate the UV industry to correct this deficiency.
[0020] Notwithstanding the uncertainly expressed in the Riley and Nordell article regarding the dangers of ultraviolet radiation, that article is actually more cognizant of those dangers than much of the other literature on the subject. For example, the article by Riley, Knight and Middlebrook, supra, does not even mention the dangers to the skin and eyes of ultraviolet radiation, or any precautions that should be taken to minimize those dangers.
[0021] There are number of ultraviolet germicidal systems that have been patented, but as in the case of the scientific literature mentioned above, those patents teach little about the dangers of ultraviolet radiation and how to effectively minimize the dangers, or how to position and operate the devices to achieve the requisite bacterial kill rate to prevent transmission of disease.
[0022] For example, U.S. Pat. No. 3,975,790 by Patterson is for an ultraviolet lamp fixture used in combination with a conventional commercial vacuum cleaner, and U.S. Pat. No. 4,087,925 by Bienek is for a sterilizing hand dryer, in which ultraviolet lights are positioned within the housing of a blower that is used to dry wet hands, where the blower is of the type commonly used in commercial restrooms. The devices of Patterson and Bienek seem to include little or nothing for light baffling to prevent leakage of allowable light to outside the housing, and the patents teach nothing about optimal flow rates, air-exchange rates or other information for the effective use of the machines. The devices are obviously intended as general, and only partially effective, sterilizing tools rather than as comprehensive and predictably effective systems.
[0023] Another patent, U.S. Pat. No. 4,210,429 by Golstein, employs a “squirrel-cage” type blower which draws air into a housing through a air intake filter, through the blower, and through a sterilization chamber containing ultraviolet lights. The air leaves the sterilization chamber, passes through a second filter and a charcoal filter and finally exits through an outlet. The specification indicates that the purpose of the device is to remove “pollens, lung damaging dust, smoke, bacteria and any one of a number of other irritants and micro-organisms” and that it does so for “particles down to 0.3 microns in size with an efficiency of 99.9%”. The device is characterized as an “air purifier” rather than as a germicidal device; the use of three distinct filters including a very fine filter for removing extremely small particles, a charcoal filter for removing odors and a pre-filter for removing particles, is distinguishable in design and function from the present invention. This extensive filtration would require a high-capacity blower to achieve any effective air exchange rate. The device is not specifically designed for destroying the tuberculosis bacteria or any other specific bacteria, although it would obviously be effective in doing so to some extent. Therefore, the patent teaches nothing about the use of the device for that purpose or the optimal flow rates or positioning of the device for that purpose.
[0024] U.S. Pat. No. 5,074,894 by Nelson is for a hospital room to quarantine patients with tuberculosis or other respiratory diseases caused by airborne pathogens. Although one embodiment of the system includes an air circulation circuit with ultraviolet lights, the patent is directed primarily toward negative pressure and filtering aspects utilizing high-efficiency particulate air filters.
[0025] Other patents describing the use of ultraviolet light as a germicide against airborne bacteria include, U.S. Pat. Nos. 4,448,750 by Fuesting, 4,896,042 by Humphreys, 4,990,311 by Hirai and 4,047,072 by Wertz, 4,990,313 by Pacosz, 3,072,978 by Minto, 4,227,446 by Sore, 3,347,0235 by Wiley, 4,786,812 by Humphreys, 4,990,311 by Hirai, 4,931,654 by Horng, 4,806,768 by Keutenedjian, 4,750,917 by Fugii, 3,757,495 by Sievers, 3,750,370 by Brauss, 3,745,750 by Arff, 3,744,216 by Halloran, 3,674,421 by Decupper, 3,576,593 by Cicirello, and 5,185,015 by Searle. Patents directed toward the use of ultraviolet light as a germicide against bacteria in water or other liquids include U.S. Pat. Nos. 4,400,270 by Hillman, 4,482,809 by Maarschalkerweerk, 5,102,450 by Stanley and 5,124,131 by Wekhof.
SUMMARY OF THE INVENTION
[0026] The present invention is an apparatus and process for destroying airborne pathogenic bacteria such as the tuberculosis bacteria. Ultraviolet lights of a sufficient intensity are positioned within a sterilization chamber where they irradiate an air stream containing the bacteria, typically in the form of suspended microdroplets of sputum. The sterilization chamber has an exit and an entrance, and a blower is positioned preferably at the exit to draw air into the entrance and through the sterilization chamber and out the exit. The air circulates behind an intake baffle and into the sterilization chamber having a set of ultraviolet lights. An outlet baffle at the opposite side of the sterilization chamber bounces the air that passes the ultraviolet lights back over the ultraviolet lights a second time, and around the outlet baffle to the fan. The fan then expels the sterilized air back into the room. The air passing through the sterilization chamber is virtually completely sterilized of viable tuberculosis bacteria by the chosen dosimetry of the system, which is achieved by appropriately sizing the sterilization chamber employing ultraviolet lights of the correct intensity, and utilizing the right air flow rate through the blower. The apparatus is configured to fit behind a wall in a room, or preferably, above a suspended ceiling. Air is drawn by a fan from the room into an intake duct and into the apparatus.
[0027] The sterilization chamber includes a filter on the intake side to filter out large particles such as dust, in order to minimize the contamination of the ultraviolet light bulbs. The filter is deliberately designed not to intercept small particles such as microdroplets, since the filter could then become a bacteria colony. The use of a low density filter also minimizes the resistance to air flow, thereby allowing the use of a smaller, more efficient and quieter blower. With the exception of this intake filter for removing large particulates, the apparatus preferably does not include any devices that would intercept and retain microdroplets or other small particles in a way that resists the air flow and poses the possibility of becoming a bacteria colonization site; the small particulates and microdroplets with destroyed bacteria simply pass through the apparatus and are expelled back into the environment.
[0028] Both the air intake and exhaust to the sterilization chamber are baffled so that ultraviolet light must reflect off multiple surfaces before exiting the sterilization chamber. The interior surfaces of the baffles may be light-absorptive to minimize their reflectivity and further lessen the possibility of ultraviolet light leaking from the sterilization chamber into the environment.
[0029] The apparatus is used in a space having a volume of air that results in an air exchange rate of preferably 12-15 air exchanges per hour. At that air exchange rate, it has been determined that a sufficient volume of air will circulate through the apparatus and will prevent any air stagnation in the room, that a high enough percentage of tuberculosis bacteria will be destroyed before they are inhaled by persons in the room to prevent transmission of the disease.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] [0030]FIG. 1 is a pictorial cutaway view of the present invention.
[0031] [0031]FIG. 2 is a side sectional view of the present invention, taken along line 2 - 2 of FIG. 1, installed in a suspended ceiling.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0032] A pictorial view of a preferred embodiment of the invention is shown in FIG. 1. The principal elements of the invention 10 include an exterior housing 40 having an air intake duct 42 and an air discharge duct 44 , a squirrel-cage type blower 120 and set of ultraviolet lights 150 in a sterilization chamber 180 within the housing 40 . The air intake duct 42 is preferably positioned at one end 46 of the housing and the air discharge duct 44 is positioned at the opposite end 47 of the housing 40 .
[0033] As better shown in the sectional view of FIG. 2, the air intake duct 42 has positioned within it a filter 60 which substantially fills the intake duct 42 so that all air drawn through the air intake duct 42 must pass through the filter 60 . The filter 60 is preferably not a high-density filter, but is instead designed to intercept and retain only fairly large particulates such as dust. The purpose of the filter 60 is not to allow the apparatus 10 to purify the air, but is merely to intercept dust over 10 microns in size that would otherwise contaminate the ultraviolet light bulbs 150 . In a preferred embodiment, the filter is model no. DP1-40, available from Airguard Industries located in Louisville, Ky. The filter 60 is retained in the air intake duct 42 by means of clips, brackets or any other suitable retention means (not shown) that allow easy removal and replacement of the filter 60 .
[0034] It is notable that in the preferred embodiment, there is no filter at all in the air discharge duct 44 or elsewhere downstream from the sterilization chamber. Therefore, the only filter in the preferred embodiment is the large particulate filter 60 positioned in the air intake duct 42 . The apparatus 10 is designed to allow small particulates, including microdroplets of sputum containing bacteria that are destroyed by the ultraviolet lights as described below, to be expelled back into the environment. As a result, the apparatus does not have a site that traps and allows the colonization of bacteria, which would require frequent cleaning or sterilization. In addition, there is very little resistance to air flow, thereby allowing the use of a relatively small, low-energy and quiet motor and blower system, as further described below.
[0035] In this respect, the present system is fundamentally different from prior art devices that are designed to remove dirt, pollen and other particulates and odor from the air. Those prior art systems employ dense and multiple filters and noisy high-energy blowers to indiscriminately remove impurities from the air. But they are not specifically for the purpose of destroying pathogenic pulmonary bacteria such as tuberculosis and their efficiency in doing so is undocumented and questionable. In contrast, the present system is specifically designed for destroying bacteria such as the tuberculosis bacteria, and is highly effective in accomplishing that using a relatively small, energy efficient, quiet apparatus, but the present system makes no attempt at all to remove impurities from the air. Even the bacteria itself is released back to the environment once it is killed by the apparatus.
[0036] The air discharge duct 44 is preferably positioned remotely from the air intake duct 42 , so that the exhausted air circulates into the environment rather than being immediately drawn back into the apparatus 10 . In the embodiment shown in FIGS. 1 and 2, the positioning of the ducts 42 and 44 on opposite ends of the housing produces a circulatory effect through the environment of the apparatus 10 by drawing air into the apparatus 10 through the air intake duct 42 and expelling air from the apparatus 10 through the air discharge duct 44 , roughly in the direction of the arrows shown in FIG. 2. The air discharge duct 44 may be covered with a grill (not shown) to prevent the introduction of hands or objects into the air discharge duct 44 and to diffuse the air stream exhausted from there. A door 183 is positioned in the bottom of the housing 40 as shown in FIG. 2 and is attached to the housing 40 by a hinge 185 or other suitable attachment means. The door is positioned to allow ready access to the ultraviolet lights 150 and to the filter 60 to allow them to be changed or cleaned.
[0037] The sterilization chamber 180 is baffled on the upstream side by an intake baffle 182 , and on the downstream side by a pair of exhaust baffles 184 and 187 , to prevent ultraviolet light from leaking from the sterilization chamber 180 out the air intake duct 42 or air discharge duct 44 and into the environment where it could damage the skin and eyes of patients and other persons. The baffles also improve the circulation of the air over the ultraviolet bulbs in the manner described below. The intake baffle 182 in the preferred embodiment is an S-shaped element fabricated from sheet metal or other appropriate material that is not degraded by ultraviolet light. The lower portion of the intake baffle 182 is curved away from the air intake duct 42 to receive the incoming air, while the upper portion of the intake baffle 182 is curved toward the sterilization chamber 180 to allow the incoming air to flow smoothly over the top of the intake baffle 182 and into the sterilization chamber 180 . The intake-baffle 182 may be attached to the housing 40 at the bottom of the intake baffle 182 or at the ends.
[0038] The exhaust baffles 184 and 187 form a channel therebetween for the air to leave the sterilization chamber 180 , as best shown in the sectional view of FIG. 2. Both exhaust baffles 184 and 187 are curved with the inner side of the curve away from the sterilization chamber 180 . The air passes under the lower edge of the upper exhaust baffle 184 , through the channel defined by the upper baffle 184 and 187 , and over the upper edge of the lower exhaust baffle 187 .
[0039] The upper exhaust baffle 184 may be attached to the housing 40 at the top of the upper exhaust baffle 184 or at the ends. The lower exhaust baffle 187 may be attached to the housing 40 at the bottom of the lower exhaust baffle 187 or at the ends.
[0040] It can be appreciated that for any ultraviolet light to escape from the sterilization chamber 180 through the air discharge duct 44 , it must reflect off the walls of the sterilization chamber 180 , reflect through the channel defined by the upper and lower exhaust baffles 184 and 187 , and then through the blower 120 and out the air discharge duct 44 . For any ultraviolet light to escape through the air intake duct 42 , it must reflect off the walls of the sterilization chamber 180 , into the space between the air intake duct 42 and the intake baffle 182 , through the air intake filter 60 and through the air intake duct 42 . The possibility of light escaping can be further reduced by applying an absorptive coating or paint to the interior surfaces of the baffles 182 , 184 and 187 and the other interior surfaces of the housing 40 .
[0041] Although the baffling described above to prevent ultraviolet light from escaping presents a circuitous route for the passage of air from the air intake duct 42 through the sterilization chamber 180 and out the air discharge duct 44 , the baffles are still designed to minimize the resistance to air flow. Thus, as shown by the arrows in FIG. 2, the air can flow reasonably smoothly with limited turbulence loses, thereby allowing a small, quiet and efficient blower system.
[0042] An important aspect of the embodiment shown in FIGS. 1 and 2 is that the baffles 182 and 184 and sterilization chamber 180 are configured such that the air passes the ultraviolet lights twice. As shown by the arrows of FIG. 2, the air passes the ultraviolet lights a first time immediately after it passes over the top of the air intake baffle 182 and into the sterilization chamber. The air pathway is blocked on the opposite side of the sterilization chamber by the air exhaust baffle 184 . The inclined and curved surface of the air exhaust baffle, together with the top wall of the housing 40 , define a space 186 to receive the air after it passes the ultraviolet light a first time. The air then reflects off the air exhaust baffle 184 and out of the space 186 and back toward the ultraviolet lights for a second pass. The air is then drawn out of the sterilization chamber 180 by passing under the exhaust baffle 184 and into the blower 120 .
[0043] The blower 120 in the preferred embodiment is of the “squirrel-cage” type. The blower 120 draws air through its ends and propels the air out the middle and into the exhaust duct 44 . The exact size of the blower and the motor for the blower depend on the desired use of the machine and the size of the environment in which it will be used, as further discussed below. The motor is preferably of the normal alternating current type and is in communication with the electrical system (not shown) of the apparatus, which also powers the ballasts for the ultraviolet lights 152 . The electrical system is ordinary, and the details of it will be apparent to those skilled in the wiring of lights and motors, and it is not further described herein.
[0044] The apparatus 10 is preferably positioned in the suspended ceiling 191 of a patient room as shown in a preferred arrangement in FIG. 2. Cutouts in the ceiling 191 are provided for the air intake duct 42 , air discharge duct 44 and access door 183 . The microdroplets from the patient are expectorated from the patient into the surrounding air where they are suspended. The air currents produced by the apparatus 10 draws air into the apparatus 10 from intake duct 42 . The filter 60 traps large dust particles, but allows small particles to pass including the micro droplets of small bacteria-containing sputum. The air with the suspended microdroplets passes through the sterilization chamber where the bacteria are destroyed by passing twice over the ultraviolet lights, and the air along with the suspended microdroplets with the then-killed bacteria are expelled from the apparatus 10 back into the room through the air discharge duct 44 . Because the air discharge duct 44 is preferably positioned at one end 46 , of the apparatus 10 while the air intake duct 42 is positioned at the other end 47 of the apparatus, the air being drawn into the air intake duct 42 and expelled from the air discharge duct 44 produces a circulatory effect through the room which increases the flow of new unsterilized air into the apparatus. This circulatory effect also helps prevent the air from short-circuiting the circulation pattern by leaving the apparatus 10 through the air discharge duct 44 and immediately re-entering the apparatus 10 through the air intake duct 42 without passing through the room.
[0045] It has been determined experimentally that transmission of the tuberculosis bacteria from an infected patient to an uninfected person can be effectively prevented by ensuring that there are approximately 10 to 15 air changes per hour in the patient room using the apparatus and positioning described above. The phrase “10 to 15 air changes per hour” means a circulatory effect through the apparatus in which the total volume of air through the apparatus per hour equals the air volume of the room multiplied times a number between 10 and 15, inclusive. For example, one air change per hour in a 1,000 cubic foot room would require an apparatus through which 1,000 cubic feet of air pass per hour. Therefore, in a patient room having dimensions of 10 by 10 by 10 feet for a total volume of 1,000 cubic feet, or other dimensions for a total volume of 1,000 cubic feet, the apparatus should be capable of circulating through it at the rate of 10,000 to 15,000 cubic feet of air per hour.
[0046] The exact dimensions of the apparatus to achieve such a flow rate in a preferred embodiment include a housing 40 having a length of about 48 inches, a height of about 15.5 inches, and a depth of about 36 inches. The air intake duct 42 is roughly 6 inches by 24 inches and the air discharge duct 44 is roughly 6 inches by 18 inches. The opening between the top of the air intake baffle 182 and the housing 40 is about 4 inches, and the opening between the bottom of the air exhaust baffle 184 and the housing 40 is about 4 inches. The motor is a 115 volt, 1,725 rpm motor, and the blower 120 includes 4 by 9 inch blower wheels. The ultraviolet lights 152 are model D-36-3 by American U.V. Co.
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A germicidal method and apparatus for destroying airborne pathogenic bacteria such as tuberculosis bacteria using ultraviolet light. Air is drawn through a filter and into a sterilization chamber that is irradiated with ultraviolet light, and out through an exhaust opening. Consideration for the characteristics of the room in which the apparatus is installed and the positioning of the installation allows effective prevention of transmission of disease through expectoration and inhalation of airborne microdroplets of bacteria-containing sputum. The filter is of the low-density type which traps large particulates, but not small particulates of the size of the microdroplets, so that the filter does not become a bacteria colonization site. Baffles on the air intake opening and air exhaust opening to prevent ultraviolet light from escaping into the environment. The sterilization chamber is constructed such that the air passes the ultraviolet light bulbs twice as it circulates therethrough.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 12/578,818, filed Oct. 14, 2009, which is a continuation of U.S. application Ser. No. 11/829,682, filed Jul. 27, 2007, now U.S. Pat. No. 7,780,726, which is a continuation of U.S. application Ser. No. 10/482,270, filed Jul. 6, 2004, now U.S. Pat. No. 7,252,682, which is the U.S. national phase under §371 of International Application No. PCT/FR02/02352, filed Jul. 4, 2002, which was published in a language other than English and which claimed priority from French Application No. 01/08898, filed on Jul. 4, 2001, the disclosures of which are hereby incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an assembly for placing a prosthetic valve in a lumen of the body, especially a heart valve, and in particular an aortic valve.
2. Background Art
Documents WO 91/17720, WO 98/29057 and EP 1 057 460 each describe an assembly, including the prosthetic valve to be implanted; a radially expandable framework, called a stent, which is able, in the expanded state, to bear against the wall of the body duct to be fitted with the valve, this bearing making it possible to immobilize this stent with respect to this wall; and means for fixing the valve to the stent. The placement of the stent permits mounting of the valve in the body duct, eliminating the need for an external access route and, thus, a direct surgical intervention.
However, major drawbacks of this technique are that it entails a risk of the valve being damaged by the balloon used to expand the stent, and it limits the force of expansion that can be imparted to the stent. This limitation has repercussions on the anchoring of the stent, making a displacement of said assembly possible. This limitation also has repercussions on the leaktightness of the stent in the area of the valvular ring which is particularly affected when calcified zones give the valvular ring an irregular form and/or a certain rigidity.
Another drawback of the prior art technique is that of directly joining the commissures of the valvules to the stent. The result of this is that an expansion of the stent, and thus of the valve, different than that intended may cause poor coaptation of the valvules and, consequently, defective functioning of the valve. The stent therefore has to undergo a predetermined expansion, which prevents or complicates adaptation of this stent to the anatomical variations.
In the case of implantation of an aortic valve, the prior art technique also has drawbacks in that it necessitates very exact positioning of the stent in the aorta so that the valve is located opposite the natural valvular ring, and it entails a risk of blocking the apertures of the coronary arteries that open out at the coronary ostia.
BRIEF SUMMARY OF THE INVENTION
The present invention aims to overcome these various drawbacks. The assembly of the present invention comprises a prosthetic valve to be implanted; a radially expandable framework, or stent, comprising at least one zone intended to be expanded to allow the stent, in the expanded state, to bear against the wall of the body duct to be fitted with the valve, this bearing making it possible to immobilize the stent with respect to this wall; and means for mounting the valve with respect to the stent, making it possible to connect the valve to the stent in such a way that the placement of the stent allows the valve to be mounted in the body duct, and expansion means such as a balloon catheter being provided to trigger expansion of the stent at the implantation site. According to the invention, the valve and the stent are designed in such a way that, at the moment when the stent is expanded, the valve is situated outside the zone or zones of the stent that are subjected to said expansion means. The invention thus consists in separating the valve and said zone or zones to be expanded, so that the expansion of the stent can be effected with an expansion force suitable for perfect anchoring of this stent in the wall of the body duct to be fitted with the valve, and without any risk of destruction or damage of the valve.
According to one possibility, the stent comprises a zone for mounting of the valve, which zone is distinct from the zone or zones of the stent to be expanded, and said mounting means connect the valve to this mounting zone. The expansion of the stent thus triggers the deployment of the valve.
According to another possibility, said mounting means are designed in such a way that the valve is axially movable with respect to the stent between a position of non-implantation, in which it is situated outside the zone or zones of the stent that are to be expanded, and a position of implantation, which it can reach after expansion of the stent in the body duct, in which it is immobilized axially with respect to the stent.
The valve can thus form a subassembly separate from the stent prior to placement of this stent in the body duct, and it can be placed in the stent once the latter has been implanted. Alternatively, the valve is connected to the stent before said stent is placed in the body duct to be treated, and consequently it is introduced into this duct with the stent; said mounting means then comprise means of displacement so that, once the stent has been expanded, the valve can be displaced between said position of non-implantation and said position of implantation.
Said mounting means can then comprise one or more of the following arrangements:
fastening members such as spikes, hooks or claws that are mounted on the valve and are able to be inserted into the wall delimiting said body duct; these fastening members can be oriented radially with respect to the valve so as to be able to be inserted into said wall upon radial deployment of the valve, or they can be oriented tangentially with respect to the valve so as to be able to be inserted into said wall upon a pivoting of the valve about its axis or upon a longitudinal movement with respect to the stent; burstable vesicles that are filled with biological adhesive or other suitable adhesive product and are placed on the outer face of the valve, these vesicles being able to burst when the valve is brought into its position of implantation, in particular by their being crushed between the valve and the stent; at least one circular or helical wire or band integrated in the peripheral wall of the valve and having a shape memory, so that it keeps the valve pressed against the stent in the position of implantation of this valve; conduits formed in, or fixed on, the peripheral wall of the valve, and rods formed on the stent, or vice versa, these rods being able to be engaged and being able to slide through these conduits as the valve moves from its position of non-implantation to its position of implantation, it being possible to provide means such as hooks in order to immobilize these conduits with respect to these rods in said position of implantation; wires can be connected to the ends of said rods and can pass through said conduits in order to easily guide these rods in these conduits.
Preferably, the means for mounting the valve with respect to the stent are designed in such a way that, beyond a threshold of expansion of the stent, they permit a different expansion of the valve and of the stent, so that a variation in the degree of expansion of the stent has no effect on the degree of expansion of the valve.
The valve is thus not connected directly to the stent and in particular is not connected to the stent in the area of the commissures of its valvules; in the expanded position of the stent, it can have a predetermined diameter appropriate to it, independently of the diameter of the stent. After implantation, the valve thus has a configuration ensuring that it functions properly irrespective of the degree of expansion of the stent, and this expansion of the stent can be adapted to the anatomical variability encountered at the implantation site.
The stent and/or the valve can comprise one or more elements limiting the maximum diameter of expansion of the valve, in particular in the area of the commissure points of this valve. These elements can be longitudinal wires belonging to the stent, or a framework element belonging to the valve.
Preferably, the valve has a peripheral wall with a diameter not constant in the axial direction, in particular a frustoconical shape whose diameter decreases in the distal direction, and the zone of the stent intended to receive this peripheral wall of the valve has a shape corresponding to that of this peripheral wall. This peripheral wall and this zone of the stent thus define a determined position of mounting of the valve in the stent, and they ensure that the valve is held in position in the stent. The stent advantageously has a middle portion with a smaller diameter than its end portions. It can in particular have the general form of two inverted truncated cones or an hourglass shape.
In the case where the assembly according to the invention permits mounting of an aortic valve, the stent is thus at a distance from the wall of the body duct, in particular by means of a conical or hourglass shape, allowing body fluid to pass to the coronary vessels in the area of the coronary ostia. The valve has a shape corresponding to that zone of the stent in whose area it is intended to be mounted.
Advantageously, the valve has a peripheral wall; the stent has, in the distal continuation of that zone of the stent intended to receive the valve, a foldable portion; this foldable portion is movable between an extended position, in which it is situated in the distal continuation of said zone, and a folded position, in which it is placed against the inner face of the peripheral wall of the valve and traps this peripheral wall between it and said zone of the stent, and retaining means are provided for keeping this foldable portion in this folded position. The peripheral wall of the valve is thus pressed against the stent, which ensures leaktightness of the valve with respect to the stent.
According to a preferred embodiment of the invention in this case, said retaining means are formed by a wire made of a material that is rigid but has a degree of elastic flexibility, for example a metal material having an undulated form and extending over the entire circumference of said foldable portion. Preferably, the stent comprises a sheath made of an impermeable biocompatible material and at least partially covering it. This sheath forms a fixation base for the valve and at the same time a means of sealing between the stent and the wall of the body duct. The sheath can advantageously have lateral openings that can be positioned opposite the coronary ostia at the time of implantation and thus avoid any zone of stagnation or non-circulation of the blood.
Advantageously, in the case where the assembly according to the invention comprises said foldable portion, this foldable portion is formed by a continuation of said sheath, forming a sleeve beyond that zone of the stent intended to receive the valve. Perfect leaktightness is thus obtained between the valve and the stent. The stent preferably has, fixed on said sheath, at least one inflatable peripheral chamber that can be inflated in order to form a seal ensuring leaktightness between the stent and the wall of the body duct to be fitted with the valve. This leaktightness is thus guaranteed notwithstanding the possible presence of calcified portions that give a cardiac ring an irregular shape.
Advantageously in this case, the stent has two inflatable peripheral chambers placed either side of that portion of the stent intended to bear against a cardiac valvular ring. The stent can have a cylindrical portion that can bear against a cardiac valvular ring, and a distal portion connected to this cylindrical portion. This distal portion at least partially forms said zone intended to receive the peripheral wall of the valve. The advantage is that said wall of impermeable biocompatible material is situated, in the area of this portion, at a distance from the wall of the body duct, that, in the case of implantation of an aortic valve, eliminates the risk of masking the coronary ostia.
The stent can also have a frustoconical or widened proximal portion whose diameter decreases in the distal direction and able, in the case of implantation of a heart valve, to bear against the wall of the ventricle or corresponding auricle of the heart. With this proximal portion it is possible to define the position of the stent, and thus subsequently of the valve, with respect to the zone of implantation. It also helps ensure complete immobilization of the stent. The stent can also have a supplementary bearing portion connected by filiform rods to said distal portion or to said cylindrical portion, these filiform rods having lengths such that this supplementary bearing portion is positioned beyond the coronary ostia. According to an additional characteristic, the stent has hooks that are movable between a retracted position, which they occupy before expansion of the stent, and a position of deployment into which they are brought upon deployment of the stent and in which they are inserted into a wall delimiting the body duct.
The stent can also have a portion near to the valvular ring, or situated opposite or on this valvular ring, and having a high radial force, that is to say a radial force able to erase the local anatomical irregularities, for example calcifications, with a view to reinforcing the leaktightness at the junction between the stent, the sheath and the wall of the treated duct. This portion can be deployed with the aid of an expansion system with a high radial force and low compliance, for example a balloon.
The above embodiments and methods of use are explained in more detail below.
BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES
FIG. 1 is a side view of an expandable framework called a stent, which forms part of the assembly;
FIG. 2 is a longitudinal section through a sheath forming part of the assembly, according to a first embodiment;
FIG. 3 is a longitudinal section through a heart valve forming part of the assembly, according to this first embodiment;
FIG. 4 is view of a detail of the stent, on an enlarged scale;
FIG. 5 is a view of another detail of the stent, on an enlarged scale, in a state of non-expansion of the stent;
FIG. 6 is a view of the same detail, in cross section along the line VI-VI in FIG. 5 ;
FIG. 7 is a view similar to FIG. 5 , in a state of expansion of the stent;
FIG. 8 and [sic] a view of the same detail, in cross section along the line VIII-VIII in FIG. 7 ;
FIG. 9 is a longitudinal section through the assembly according to the invention, after implantation in an aorta;
FIG. 10 is a longitudinal section through the sheath and the valve forming part of the assembly according to the invention, in a second embodiment, with the catheter used for introducing the valve into this sheath;
FIG. 11 is a perspective view of the valve according to the second embodiment;
FIG. 12 is a view similar to FIG. 10 , after placement of the valve;
FIG. 13 is a view, similar to FIG. 9 , of the assembly according to a third embodiment;
FIG. 14 is a perspective view of the valve that can be placed in the stent shown in FIG. 13 , and
FIGS. 15 through 17 are views of the assembly according to the third embodiment, in cross section on lines XV-XV, XVI-XVI and XVII-XVII, respectively, in FIG. 13 .
DETAILED DESCRIPTION OF THE INVENTION
In embodiments described herein, those elements or parts that are identical or similar and are found again from one embodiment to another are designated by the same reference numbers.
FIGS. 1 through 3 show, respectively, an expandable framework 2 called a stent, a sheath 3 , and a prosthetic valve 4 . This stent 2 , this sheath 3 and this valve 4 form an assembly 1 , which can be seen in FIG. 9 , allowing the valve 4 to be placed in an aorta 100 , showing the location of the coronary ostia 101 and the origin of the coronary vessels 104 .
Referring to FIG. 1 , it will be seen that the stent 2 comprises in succession, from one axial end to the other, in the proximal to distal direction, a frustoconical proximal portion 10 , a proximal cylindrical portion 11 , a distal frustoconical portion 12 , several connection rods 13 , and a distal cylindrical portion 14 .
This stent 2 is made of a metal, steel or alloy with shape memory. This shape-memory material can in particular be the one known by the brand name Nitinol.
The portions 10 through 12 and 14 are made up of a network of filaments forming juxtaposed meshes of diamond shape or, for portion 10 , of triangle shape. The material from which the stent 2 is made is such that these meshes can pass from a contracted configuration, in which the filaments are near one another, giving the meshes an elongate shape, to an expanded configuration, shown in FIG. 1 and in detail in FIG. 7 , in which the filaments are spaced apart from one another.
In the contracted configuration, the assembly 1 can be introduced into the aorta 100 by means of a catheter, as far as the zone in which the prosthetic valve 4 is to be implanted; in the expanded configuration, the stent 2 bears against the aorta 100 , the wall 102 of the ventricle and the natural valvular ring 103 in the manner shown in FIG. 9 , such that it permits implantation of the valve 4 in place of the natural valve, the latter having been removed beforehand if necessary.
Referring to FIGS. 1 and 9 , it will be seen that the portion 10 has a diameter decreasing in the distal direction, this portion 10 being configured so that, in the expanded state, it bears against the wall 102 of the ventricle of the heart.
In the expanded state, the portion 11 has a diameter such that it is able to bear against the natural valvular ring 103 and a radial force such that it can push the natural valve (or its remnants after partial exeresis) against the ring 103 in order to ensure leaktightness at this site. This portion 11 has deployable hooks 15 , shown more particularly in FIGS. 5 through 8 . These hooks 15 permit anchoring of the stent 2 in the aorta 100 via the sheath 3 .
As is shown in FIGS. 5 and 6 , each hook 15 extends in the longitudinal direction of a mesh, being connected in a pivotable manner to a proximal zone 16 of connection of two proximal filaments 17 . This hook 15 has a curved and tapered free end 15 a , and a face 15 b directed to the inside of the stent 2 and of rounded shape. The distal zone 18 of connection of the two other filaments 19 that is situated opposite the base of the hook 15 is able to bear, during expansion of the stent 2 , on this face 15 b , as will be inferred from comparison of FIGS. 6 and 8 . The fact that this zone 18 bears along this face 15 b makes it possible to deploy the hook 15 radially outward of the stent 2 and maintain this hook 15 in the deployed position in which its tapered end 15 a is inserted into the wall of the ring 103 . The hooks can have a fishhook shape in order to prevent their removal.
The portion 12 is directly connected to the portion 11 and has a diameter decreasing in the distal direction. This portion 12 is intended to extend to the area of the coronary ostia 101 and to receive the valve 4 . Its frustoconical shape means it is possible to keep the sheath 3 at a distance from the coronary ostia 101 and thus prevent any risk of covering the apertures 104 of the coronary vessels that open out in these.
The portion 12 additionally comprises a series of internal arms 25 , shown more particularly in FIG. 4 . Each arm 25 is connected via its proximal end to a junction zone 16 of two proximal filaments 17 of a mesh, in proximity to the portion 11 , and has a curved distal end 25 a . These arms 25 are inclined toward the inside of the portion 12 before placement of the valve 4 on the stent 2 , and FIG. 4 shows that in this position they can receive the valve 4 . The latter actually comprises a peripheral wall 30 in which there are longitudinal tunnels 31 thr receiving the arms 25 ; these can then be folded back against the wall of the portion 12 , either by deformation of the material constituting the arms 25 and/or the portion 12 , or by shape memory when use is made of a material with shape memory. These arms 25 thus allow the valve 4 to be mounted in the portion 12 , as is shown in FIG. 9 .
The connection rods 13 connect the distal edge of the portion 12 to the proximal edge of the portion 14 . They are arranged uniformly on the periphery of the stent 2 and, as is shown in FIG. 9 , they have a length that is sufficient to ensure that the portion 14 is placed, after implantation, beyond the coronary ostia 101 . The spacing of these rods 13 can be curbed by an annular element making it possible to limit the upper diameter of the valve 4 to a predefined size.
The portion 14 for its part has, in the expanded state, a slightly greater diameter than the internal diameter of the aorta 100 , and it bears against the wall of the latter once the stent 2 has been put in place. This portion 14 can be equipped with hooks 15 .
The sheath 3 is made of an impermeable biocompatible material, such as pericardial tissue, material known under the name Dacron, or a polymer such as polyurethane, and it has portions 35 , 36 and 37 . These portions 35 , 36 and 37 can be connected, respectively, to the portions 10 , 11 and 12 and can closely match these portions 10 through 12 when the latter are in the expanded state. The connection between the sheath 3 and the portions 10 through 12 is formed by seams when the assembly 1 is assembled. The connection can also be effected by molding of a polymer material.
At the proximal end, the sheath 3 has a flap 40 extending on the outer face of the portion 35 . This flap 40 has, near its free edge, an inflatable peripheral chamber 41 . This chamber 41 can be inflated so as to form a seal ensuring leaktightness between the sheath 3 and the wall of the ventricle 102 , on the proximal side of the natural valvular ring 103 .
At the distal end, the sheath 3 has a flap 42 extending on the outer face of the portion 12 . Near its free edge, this flap 42 comprises an inflatable peripheral chamber 43 , similar to the chamber 41 and able to be inflated in the same way as the latter. This chamber 43 ensures leaktightness between the sheath 3 and the ring 103 , on the distal side of the latter.
It will be seen from FIG. 2 that the flap 42 forms a distal sleeve 45 extending beyond the distal edge of the portion 12 , and it is clear from FIG. 9 that this sleeve 45 can be folded back inside the portion 12 . This sleeve 45 includes a metal wire 46 extending over the entire circumference, this wire 46 having an undulated shape and being elastically deformable. The deformability of this wire 46 allows the sleeve 45 to pass from its extended position shown in FIG. 2 to its folded position shown in FIG. 9 , in which it is maintained by elastic return of the wire 46 . In this folded position, the sleeve 45 is placed against the inner face of the peripheral wall 30 of the valve 4 and traps this wall 30 between it and said portion 12 .
The valve 4 can be made of a biological material or of a synthetic material, or of a combination of these two types of materials. Its peripheral wall 30 has a frustoconical shape adapted to its tight engagement in the portion 12 when the arms 25 are folded back against this portion 12 , which ensures complete immobilization of the valve 4 in the stent 2 .
The assembly 1 is assembled by placing the sheath 3 on the stent 2 and placing the valve 4 on the arms 25 , the stent 2 being in the contracted state. The assembly 1 is then placed in a catheter permitting its introduction into the patient's body, this catheter including one or more inflatable balloons able to deploy the portions 10 , 11 and 14 . This catheter is then brought into position in the aorta 100 . The balloons are then inflated in order to deploy the portions 10 , 11 and 14 ; the forced deployment of the portion 11 by the balloons ensures the deployment of the hooks 15 and triggers deployment of the portion 12 , and consequently of the valve 4 . The chambers 41 , 43 are then inflated to ensure leaktightness of the sheath 3 with respect to the ring 103 , and the sleeve 45 is folded back inside the portion 12 in order to clamp the peripheral wall 30 of the valve 4 against this portion 12 .
As will be apparent from the above, the valve 4 and the stent 2 of the assembly 1 are designed in such a way that the valve 4 is situated outside the zone or zones 10 , 11 , 14 to be expanded. The stent 2 can be expanded with a force of expansion adapted for perfect anchoring of this stent 2 in the receiving walls 100 , 102 , 103 , and without any risk to the valve 4 . The hooks 15 ensure complete immobilization of the assembly 1 in the aorta 100 , and the chambers 41 , 43 , and also the sleeve 45 , ensure complete leaktightness of the assembly 1 with respect to the aorta 100 .
In the second embodiment of the assembly 1 , the valve 4 is not mounted in advance inside the stent 2 but is placed in it once the stent 2 has been expanded. As is shown in FIG. 10 , the sheath 3 then has internal tubes 50 formed in such a way as to protrude inside the stent 2 once this sheath 3 is engaged on the stent 2 . These tubes 50 can in particular be sewn or fixed by any other means to the sheath 3 after the latter has been placed on the stent 2 .
Referring to FIG. 11 , it will be seen that the peripheral wall 30 of the valve 4 has, in place of the tunnels 31 , a series of pin-shaped clips 51 . Each clip 51 has an inner arm 52 engaged longitudinally in the wall 30 , and a rectilinear outer arm 53 extending along the outer face of the wall 30 . The arms 53 terminate in curved ends and are connected to wires 55 engaged and able to slide in the tubes 50 .
As is shown in FIG. 10 , a catheter 80 is used to bring the valve 4 into position in the sheath 3 . The valve 4 is engaged with sliding on the catheter 80 , and the wires 55 , after passing through the tubes 50 , are engaged in the catheter 80 from the direction of the distal opening thereof and pass through this catheter 80 in order to be actuated from the outside. The valve 4 is put into place and deployed by pulling on the different wires 55 so as to engage the different arms 53 in the tubes 50 . The inner arms 52 can comprise (see FIG. 12 ) proximal hooks that complete the deployment of the valve 4 by being fastened to the wall of the sheath 3 , for example by means of inflation of a balloon.
In the third embodiment of the assembly 1 shown in FIG. 13 , the stent 2 forms a median cage delimited by a ring 60 and by longitudinal wires 61 , in which cage the valve 4 is tightly inserted. As is shown in FIG. 14 , the valve 4 has a lateral wall 30 of tubular shape in which three lateral openings 65 are formed. These openings 65 are positioned opposite the coronary ostia 101 and permit a natural flow of blood, without risk of stagnation in the area of these coronary ostia 101 .
The invention provides an assembly 1 for placing a valve 4 in a body duct 100 , said assembly having the following advantages over similar assemblies in the prior art: elimination of the risk of damage to the valve 4 by the balloon or balloons used to expand the stent 2 ; possibility of applying a considerable force of expansion to the stent 2 , that ensures the anchoring of the assembly 1 ; this considerable force of expansion additionally permits this anchoring by means of the deployable hooks 15 ; elimination of the risk of dilation of the valve 4 beyond a diameter no longer permitting its optimal functioning, in particular through loss of coaptation of the valvules; possibility of obtaining perfect leaktightness of the assembly 1 in the area of the valvular ring 103 and of the valve 4 ; elimination of the risk of blocking of the coronary ostia 101 ; and maintenance of a flow of body fluid all around said assembly 1 once the latter is implanted.
It goes without saying that the invention is not limited to the embodiment described above by way of example, and that instead it encompasses all alternative embodiments thereof coming within the scope of protection defined by the attached claims.
It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor(s), and thus, are not intended to limit the present invention and the appended claims in any way.
The present invention has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.
The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.
The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.
The claims in the instant application are different than those of the parent application or other related applications. The Applicant therefore rescinds any disclaimer of claim scope made in the parent application or any predecessor application in relation to the instant application. The Examiner is therefore advised that any such previous disclaimer and the cited references that it was made to avoid, may need to be revisited. Further, the Examiner is also reminded that any disclaimer made in the instant application should not be read into or against the parent application.
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A prosthetic valve assembly can include a radially expandable stent. The stent can include a first expandable annular portion that is configured, in an expanded state, to bear against a wall of a native body lumen, a second expandable annular portion that is configured, in an expanded state, to bear against a wall of a native body lumen. The stent can also include a plurality of rods extending between the first annular portion and the second annular portion. The prosthetic valve assembly can further include an implantable prosthetic valve mounted to the stent such that the valve is between the first annular portion and the second annular portion. The prosthetic valve assembly is configured to be delivered by catheterization.
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TECHNICAL FIELD
[0001] The presently disclosed embodiments are generally directed to nail polish compositions. These compositions are odor-free and aqueous-based to provide a nail polish composition that are both safer and more environmentally-friendly to use. In embodiments, the present compositions include, but are not limited to, color enamels, nail varnishes, nail lacquers, clear base coats, topcoats, and nail hardeners.
BACKGROUND
[0002] Generally, conventional nail polish compositions have a base composition of organic solvents containing a resin or primary film-forming agent, an aryl-sulfamide formaldehyde resin, or an alkyd resin, and a plasticizing agent. The resins are often ones including nitrocellulose, polyacrylates, styrene-acrylates, polyurethanes, polyester urethanes, and the like. These resins all have unwanted residual monomers or isocyanate residual and are used in combination with organic solvents to enable film formation.
[0003] In particular, nitrocellulose provides good adhesion of the compositions to nails upon application, and is the preferred conventional film-forming agent for use in nail polish compositions. Nitrocellulose, however, is highly flammable, and thus, may pose safety hazards during the manufacturing process for nail polish compositions that require the use of nitrocellulose. Additionally, the solvents used to dissolve nitrocellulose such as toluene, isopropanol, ethyl acetate, butyl acetate or mixtures thereof, are also flammable and have unpleasant odor. As such, alternatives to nitrocellulose, which provide good adhesion to nails but which avoid the negative issues associated with nitrocellulose, are sought to either reduce the amount of nitrocellulose used in the composition or entirely replace the nitrocellulose in the composition.
[0004] Other common components of nail polish such as formaldehyde, toluene and phthalate help provide a product that is long-lasting and fast drying. These components provide the nail polish with desirable attributes: toluene allows dilution of the resin and fast drying time of the polish, formaldehyde provides cross linking with keratin and offers good cohesion, and phthalate increases homogeneity of the film. However, the toxicity of these compounds is pushing cosmetic companies to identify alternative technologies while keeping the original attributes.
[0005] It has also been discovered that the use of aqueous-based nail polish compositions may help avoid the problems associated with conventional, organic solvent-based compositions. Aqueous compositions avoid much of the problem associated with non-aqueous compositions, such as, smell, toxicity to environment and damage to the nail. The problem with aqueous-based nail polish compositions, however, is that such compositions are generally slow to dry. Thus, such compositions would benefit from faster setting film-forming agents.
[0006] Therefore, there exists a need for new film-forming agents to be used in aqueous nail polish compositions which may reduce or replace the amount of organic solvents and nitrocellulose needed—providing a safer and more environmentally-friendly composition. Moreover, the resulting nail polish composition is preferably free of formaldehyde, toluene and phthalate. In aqueous-based compositions, such film-forming agents should be faster setting to help provide a nail polish composition that is not slow drying and still maintain good adhesion and glossiness.
BRIEF SUMMARY
[0007] According to embodiments illustrated herein, there is provided a nail polish composition that avoids the problems associated with conventional nail polish compositions, as discussed above.
[0008] An embodiment may include an aqueous-based nail polish composition, comprising: an emulsion of a sulfonated polyester resin in water; and an optional pigment; and an optional thickening agent.
[0009] In another embodiment, there is provided an aqueous-based nail polish composition, comprising: an emulsion of a sulfonated polyester resin in water; and an optional pigment, wherein the sulfonated polyester resin is selected from the group consisting of a sodio-sulfonated polyester resin, a sodio-sulfonated co-polyester-co-polysiloxane resin and mixtures thereof.
[0010] In yet further embodiments, there is provided an aqueous-based nail polish composition, comprising: an emulsion of a branched sulfonated polyester resin in water; and an optional pigment, wherein the aqueous-based nail polish composition is odorless and has a viscosity at 25° C. of from about 5 to about 5,000 cps.
[0011] Finally, in embodiments, there is provided a method of preparing an aqueous-based nail polish composition, comprising: adding a sulfonated polyester resin to water; emulsifying the-sulfonated polyester resin in water to obtain an emulsification; and adding an optional pigment to the emulsification to obtain an aqueous-based nail polish composition.
DETAILED DESCRIPTION
[0012] In the following description, it is understood that other embodiments may be used and structural and operational changes may be made without departing from the scope of the present disclosure.
[0013] In the present embodiments, there are provided nail polish compositions that comprise particular anionic polyester resins as the film-forming agent. The resins include highly viscous ones such as sulfonated polyester (SPE). Particular embodiments include sodio-sulfonated polyesters and sodio-sulfonated co-polyester-co-polysiloxanes.
[0014] These resins are odor-less, unlike styrene-acrylates, and non-toxic unlike polyurethanes (derived from isocyanates). Moreover, the sodio-sulfonated polyesters and sodio-sulfonated co-polyester-co-polysiloxane dissipate (or emulsify) readily in water (at temperatures greater than 85° C.) to form emulsions with particle sizes in the desired range of from about 10 to about 300 nm. The resulting emulsions form robust films after drying.
[0015] Fingernails and toenails are made of a tough protein called keratin, which is a family of fibrous structural proteins that are typically inert and water-insoluble. A sclera-protein occurs as an aggregate due to hydrophobic side chains that protrude from the molecule. The proteins comprise of peptide sequence such as a collagen helix, which feature cross-links between chains (e.g., cys-cys disulfide bonds between keratin chains). Overall, these surfaces tend to be cationic due to amide bonds of the peptide sequence. The anionic properties of the polyester resins of the present embodiments bind easily to the nail (cationic proteins).
[0016] The present nail polish compositions provide a number of attributes, including being long-lasting (remains on nails for a minimum of 5 days, and in some embodiments, a minimum of 7 days), having the ability to form a homogeneous film on nails, compatible with inorganic pigments, providing shiny, glossy coat, fast-drying (for example, drying within 80 seconds), being odorless, being safe for application to human nails and being easy to apply. In addition, because the present compositions avoid many of the organic solvents used in conventional nail polish compositions, the present compositions are much more gentler on the nails and nail components.
[0017] In embodiments, the nail polish composition comprises a sulfonated polyesters of the formula or as essentially represented by the formula:
[0000]
[0000] wherein M is a Hydrogen or Alkali metal such as lithium or sodium, and R 1 and R 3 is independently selected from the group consisting of aryl and alkyl; R 2 is independently selected from the group consisting of alkyl and oxyalkylene, and wherein n and p represent random segments of the polymer; and are each about 10 to about 100,000 units. In embodiments, R 1 is selected from the group consisting of terephthalyl, isophthalyl, phthalyl, xylyl, 1,4-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclohexyl, 1,4-naphthyl, 1,7-naphthyl, 1,6-naphthyl, 1,3 naphthyl, 1,2-naphthyl, 1,8-naphthyl, and biphenyl. In embodiments, R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, stearyl, lauryl, neopentyl, 1,2-propyl, 1,2-butyl, 1,3-butyl, 2-pentyl, 2,2-dimethylpropyl, and an oxyalkylene of diethyleneoxide, dipropyleneoxide, triethyleneoxide, and mixture thereof. In another embodiment, the nail polish composition comprises a sulfonated co-polyesters-copolysiloxane of the formula or as essentially represented by the formula:
[0000]
[0000] wherein M is a hydrogen or alkali metal such as lithium or sodium, and R 1 and R 3 is independently selected from the group consisting of aryl and alkyl; R 2 is independently selected from the group consisting of alkyl and oxyalkylene, and wherein a, b, c, n and p represent random segments of the polymer; and are each about 10 to about 100,000 units In embodiments, R 1 is selected from the group consisting of terephthalyl, isophthalyl, phthalyl, xylyl, 1,4-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclohexyl, 1,4-naphthyl, 1,7-naphthyl, 1,6-naphthyl, 1,3 naphthyl, 1,2-naphthyl, 1,8-naphthyl, and biphenyl. In embodiments, R 2 and R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, stearyl, lauryl, neopentyl, 1,2-propyl, 1,2-butyl, 1,3-butyl, 2-pentyl, 2,2-dimethylpropyl, and an oxyalkylene of diethyleneoxide, dipropyleneoxide, triethyleneoxide, and mixture thereof.
[0018] In general embodiments, the sulfonated polyester is derived from at least one dicarboxylic acid, at least one diol and at least one component of a sulfonated ion attached to a dicarboxylic acid or diol component. In particular embodiments, the sulfonated polyester is derived from dimethyl terephthalate, dimethyl-5-sulfo-isophthalate sodium salt, 1,2-propanediol and diethylene glycol. In further embodiment, the sulfonated co-polyesters-copolysiloxane is derived from at least one dicarboxylic acid, at least one diol and at least one component of a sulfonated ion attached to a dicarboxylic acid or diol component. In particular embodiments, the sulfonated polyester is derived from dimethyl terephthalate, dimethyl-5-sulfo-isophthalate sodium salt, 1,2-propanediol and diethylene glycol, and a bis-carbinol terminated polydimethylsiloxane such as Bis-3-propyl-polydimethylsiloxane available from Gelest Inc, and of the formula;
[0000]
[0000] wherein c represents the number of repeat units and is an integer of from about 10 to about 100,000.
[0019] In further embodiments, the dicarboxylic acid or diester is selected from the group consisting of terephthalic acid, phthalic acid, isophthalic acid, fumaric acid, maleic acid, succinic acid, itaconic acid, succinic anhydride, succinic anhydride, dodecylsuccinic acid, dodecylsuccinic anhydride, glutaric acid, glutaric anhydride, adipic acid, pimelic acid, suberic acid, azelic acid, dodecanediacid, dimethyl terephthalate, diethyl terephthalate, dimethylisophthalate, diethylisophthalate, dimethylphthalate, phthalic anhydride, diethylphthalate, dimethylsuccinate, dimethylfumarate, dimethylmaleate, dimethylglutarate, dimethyladipate, dimethyl dodecylsuccinate, and mixtures thereof. In such embodiments, the diol is selected from the group consisting of ethanediol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, pentanediol, hexanediol, 2,2-dimethylpropanediol, 2,2,3-trimethylhexanediol, heptanediol, dodecanediol, bis(hyroxyethyl)-bisphenol A, bis(2-hyroxypropyl)-bisphenol A, 1,4-cyclohexanedimethanol, 1,3-cyclohexanedimethanol, xylenedimethanol, cyclohexanediol, diethylene glycol, bis(2-hydroxyethyl) oxide, dipropylene glycol, dibutylene, and mixtures thereof. In embodiments, polyfunctional acid and alcohols can also be utilized to provide with branched polyester compositions, and wherein such polyfunctional acids are comprised of trimellitic anhydride, trimellitic acid, glycerol, trmethylolprpane mictures thereof and the like.
[0020] In the present embodiments, the sulfonated component is comprised of hydrogen, ammonium, lithium, sodium, potassium, cesium, berylium, magnesium, calcium, barium, strontium, iron, copper, vanadium, chromium, manganese, and cobalt of the sulfonated difunctional monomer dimethyl-5-sulfo-isophthalate, dialkyl-5-sulfo-isophthalate-4-sulfo-1,8-naphthalic anhydride, 4-sulfo-phthalic acid, dimethyl-4-sulfo-phthalate, dialkyl-4-sulfo-phthalate, 4-sulfophenyl-3,5-dicarbomethoxybenzene, 6-sulfo-2-naphthyl-3,5-dicarbomethoxybenzene, sulfo-terephthalic acid, dimethyl-sulfo-terephthalate, 5-sulfo-isophthalic acid, dialkyl-sulfo-terephthalate, sulfoethanediol, 2-sulfopropanediol, 2-sulfobutanediol, 3-sulfopentanediol, 2-sulfohexanediol, 3-sulfo-2-methylpentanediol, 2-sulfo-3,3-dimethylpentanediol, sulfo-p-hydroxybenzoic acid, N,N-bis(2-hydroxyethyl)-2-amino ethane sulfonate, or mixtures thereof. In more particular embodiments, the sulfonated polyester is comprised of M+ ions of random copoly(ethylene-terephthalate)-copoly-(ethylene-5-sulfo-isophthalate), copoly(propylene-terephthalate)-copoly-(propylene-5-sulfo-isophthalate), copoly(diethylene-terephthalate)-copoly-(diethylene-5-sulfo-isophthalate), copoly(propylene-diethylene-terephthalate)-copoly-(propylene-diethylene-5-sulfoisophthalate), copoly(propylene-butylene-terephthalate)-copoly(propylene-butylene-5-sulfo-isophthalate), copoly(propoxylated bisphenol-A-fumarate)-copoly(propoxylated bisphenol A-5-sulfo-isophthalate), copoly(ethoxylated bisphenol-A-fumarate)-copoly(ethoxylated bisphenol-A-5-sulfo-isophthalate), copoly(ethoxylated bisphenol-A-maleate)copoly(ethoxylated bisphenol-A-5-sulfo-isophthalate), and mixtures thereof. In a specific embodiment, the sulfonated component is dimethyl 5-sulfo-isophthalate sodium salt.
[0021] Sulfonated polyesters and sulfonated co-polyester-co-polysiloxane were previously explored in toner applications, such as for example, in U.S. Pat. Nos. 5,348,832, 6,384,108, and 6,818,723, which are hereby incorporated by reference in their entireties, and found to provide excellent fusion to papers. The incorporation of such resins into nail polish compositions resulted in many unexpected benefits.
[0022] The disclosed anionic polyester resins are emulsified in water to produce an emulsion. The emulsions produced have particle sizes in the desired range of from about 10 to about 500 nm, or from about 10 to about 300 nm, or from about 10 to about 250 nm. In embodiments, the anionic polyester resin is present in the composition in an amount of from about 1 to about 80 percent, or from about 1 to about 35 percent, or from about 1 to about 15 percent by weight of the total weight of the nail polish composition. In embodiments, the water is present in the composition in an amount of from about 1 to about 95 percent, or from about 10 to about 80 percent, or from about 25 to about 75 percent by weight of the total weight of the composition.
[0023] The resulting nail polish composition has a viscosity at 25° C. of from about 1 to about 10,000 cps, or of from about 1 to about 1,000 cps. or of from about 1 to about 100 cps. The viscosity was measured on a RFS3 controlled strain Rheometer (from TA Instruments, Inc.) equipped with a Peltier heating plate and using a 25 mm parallel plate at 25 degrees centigrade. The composition dries in less than 80 seconds, or from about 10 to about 80 seconds, or from about 10 to about 50 seconds. The composition provides a glossiness of from about 20 to about 120, or from about 60 to about 90 gloss units as measured by the Gardner Gloss Metering Unit. The composition also provides a satisfactory adhesion as measured by the Hofman Scratch-hardness tester. The nail polish composition of the present embodiments resulted in similar scratch and hardness to conventional nail polish compositions.
[0024] The nail polish compositions according to the present embodiments may also contain at least one thickening agent in a proportion of from 0.01% to 5%, and preferably between 0.1% and 1%, by weight of the total weight of the polish. Thickening agents proving suitable for the aqueous nail polish formulation include cellulose and the derivatives thereof, such as carboxymethylcellulose and hydroxyethylcellulose, silicates, clays such as laponite, synthetic polymers such as acrylic or associative polyurethane-type polymers, and natural gums, such as carrageenan or xanthane gum. A thickening agent chosen from among hydroxyethylcellulose, laponite, and the associative polyurethanes is preferably selected.
[0025] Other finely ground (having a particle size not to exceed 50 microns) water-soluble inorganic powders may be used, such as boron nitride, smectite clays, silica, zinc oxide, iron oxides, calcium and magnesium carbonates, and lakes. Because lakes are available commercially in various colors as FDA-approved products for nail polishes (such as the various aluminum, zirconium, barium, strontium, potassium and calcium lakes sold by chemical companies such as Universal Foods Corporation of Plainfield, N.J., and Seltzer Chemicals Inc. of Carlsbad, Calif.), they are particularly useful as thickening agents for colored nail polishes.
[0026] Finely ground, water-insoluble organic powders are also suitable thickening agents for sulfonate-containing polymers dispersed in water. These agents comprise microcrystalline cellulose, polyaromatic amides (sold by The DuPont Company under the trademark “Kevlar”), polyethylene, nylon, and polyester, used either alone or in combination with the finely ground inorganic material described above
[0027] When the nail polish compositions according to the present embodiments are colored, they then contain at least one organic or inorganic pigment in a proportion of between 0.01% and 5% by weight, and preferably between 0.5% and 2% by weight of the total weight of the polish. Such pigments may include colors such as red, yellow, magenta, black, green, orange, pink, blue, purple, brown and mixtures thereof. For example, organic pigments include D and C Red, Nos. 10, 11, 12 and 13, D and C Red No. 7, D and C Red Nos. 5 and 6, D and C Red Nos, 30 and 34, lacquers such as D and C Yellow No. 5 and D and C Red No. 2, or guanine. The group of inorganic pigments comprises titanium dioxide, bismuth oxychloride, brown iron oxide, and the red iron oxides. The nail polish composition may also be clear, for example, free or substantially free of pigments to provide a clear coat over the nail.
[0028] Moreover, it is possible to adjust the spreadability of the polishes by using water-soluble fluorinated surfactants, including perfluoroalkyl compounds sold under the trade names FORAFAC 1179, FORAFAC 1098, FORAFAC 1157, ZONYL-FSN (DuPont Company), ZONYL FSC (DuPont Company), ZONYL FSP (DuPont Company), ZONYL UR (DuPont Company), FLUORAD FC 129 (3M Company), FLUORAD FC 135 (3M Company), FLUORAD FC 170C (3M Company), FLUORAD FC 120 (3M Company), FLUORAD FC 143 (3M Company), and the like and mixtures thereof. The proportion of water-soluble fluorinated surfactants may be between 0.01 and 1% by weight, and preferably between 0.05 and 0.2% by weight, of the total weight of the nail polish.
[0029] The nail polish compositions according to the present embodiments may further contain at least one additive selected from among a wetting agent, a dispersing agent, an anti-foaming agent, a sunscreen, a preservative, a drying-acceleration agent, a wax, a silicone, or a mixture thereof.
[0030] As discussed above, the final composition can bind to the cationic proteins on human nail surfaces. Data shows that the present composition is equivalent to the conventional nail polishes in film forming, adhesion and gloss.
EXAMPLES
[0031] The examples set forth herein below and are illustrative of different compositions and conditions that can be used in practicing the present embodiments. All proportions are by weight unless otherwise indicated. It will be apparent, however, that the present embodiments can be practiced with many types of compositions and can have many different uses in accordance with the disclosure above and as pointed out hereinafter. The resins used in these examples are defined below:
Example 1
[0032] Black Nail Polish Derived from Sodio Sulfonated Polyester Resin and Carbon Black
[0033] Sodio-sulfonated polyester resin, as prepared and described in U.S. Pat. No. 5,348,832, which is hereby incorporated by reference in its entirety, was heated in water at 85-90° C. to provide with an emulsion of about 35% solids in water. In a 50 mL beaker, the emulsion was added (5.68 g) followed by carbon black 300 (4.35 g, available from Cabot Corp.). The mixture was stirred with a magnetic stir bar at room temperature for about 10 minutes to give a homogenous formulation.
Example 2
[0034] Black Nail Polish Derived from Sodio Sulfonated Co-Polyester Co-poly-Siloxane Resin and Carbon Black
[0035] An aqueous emulsion of sodio sulfonated co-polyester co-poly-siloxane resin, as prepared and described in U.S. Pat. No. 6,818,723, which is hereby incorporated by reference in its entirety, was heated in water at 85-90° C. to provide with an emulsion of about 21% solids in water. In a 50 mL beaker, the emulsion was added (6.83 g) followed by carbon black 300 3.17 g, available from Cabot Corp.). The mixture was stirred with a magnetic stir bar at room temperature for about 10 minutes to give a homogenous formulation.
Example 3
[0036] Magenta Nail Polish Derived from Sodio Sulfonated Co-Polyester Co-Poly-Siloxane Resin and Magenta Pigment
[0037] The nail polish composition for this example was prepared in the same way as Example 2 except that magenta pigment was used in place of carbon black as shown in Table 1 below.
Examples 4-5
[0038] Red Nail Polish Derived from Sodio Sulfonated Co-Polyester Co-Poly-Siloxane Resin
[0039] Nail polish compositions of these examples were prepared in the same way as Example 2 except that red pigment was used in place of carbon black as shown in Table 1 below.
[0000]
TABLE 1
Ex-
Ex-
Ex-
Ex-
Ex-
ample
ample
ample
ample
ample
1
2
3
4
5
Sodio-Sulfonated
19.30
polyester resin
BSPE (33.95%
solids)
Sodio Sulfonated
14.06
14.06
14.06
24.06
co-Polyester
co-poly-
siloxane Resin
(20.60% solids)
Cabo-jet 300
6.47
4.71
(carbon Black)
Cabo-jet 480 V
4.71
(magenta)
Sun Chemical
4.71
4.71
MCM-059-SJ
(Red)
Water
74.24
81.23
81.23
81.23
71.23
Total
100.00
100.00
100.00
100
100.00
Viscosity 25° C.
2.32
2.11
2.14
7.46
(cps)
Drying Time
<80
<80
<80
<80
(seconds)
Image Robustness
Poor
Excellent
Excellent
Excellent
(done visually
and compared to
commercial nail
polish)
Nail Polish Composition Performance
[0040] The polish obtained by the above compositions spread easily on the nail and allowed to dry. Drying time was assessed by time required for all the water to evaporate leaving robust film that could not be easily removed by rubbing with a Q-tip. Image robustness was assessed by removing the nail Polish by rubbing with a Q-tip.
[0041] Water-resistance of the polish obtained was analyzed by applying a 300 μm film on a glass plate, then by immersing it for one hour while stirring in cold or hot (45° C.) water, with or without detergent. No discoloration was then observed, nor were any tearing or dissolution of the film over time noted. The polish obtained thus had excellent water-resistance, in particular to hot water, even in the presence of a detergent.
[0042] The composition provides comparable glossiness, as measured by the Gardner Gloss Metering Unit, and comparable scratch and hardness, as measured by the Hofman Scratch-hardness tester, to conventional nail polish compositions.
[0043] It will be appreciated that various of the above-disclosed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Various presently unforeseen or unanticipated alternatives, modifications, variations, or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.
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Personal care products for maintaining fingernail and toenail appearance. In particular, nail polish compositions that have a formulation that is both safer and more environmentally-friendly to use. The present nail polish compositions comprise anionic polyester resins such as sodio-sulfonated polyesters and sodio-sulfonated co-polyester-co-polysiloxane copolymers as base resin vehicles.
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FIELD OF THE INVENTION
The present invention relates to an in-vivo animal model useful in identifying novel therapies for treating infectious diseases. In particular, the invention relates to a C. elegans infection model for evaluating the ability of a chemical to disrupt colonization and disease caused by E. coli pathogens.
BACKGROUND
Resistance to chemotherapeutic agents is rendering previously life-saving drugs useless. Perhaps most alarming, multi-drug resistant bacteria are commonplace in hospital settings and lead to untreatable infections. There is a clear need to develop novel, effective therapies against infectious disease. In addition to compounds that kill pathogenic organisms, anti-infectives, or agents that block or disrupt infection, show promise for eliminating disease without killing the organisms.
Anti-infectives are drugs that target the host-microbe interaction, instead of simply targeting the microbe. Anti-infective drugs may enhance and extend the usefulness of the antibiotics currently available by minimizing selective pressure, which leads to resistance. Using small molecules to block bacterial attachment, or to mask host cell receptors specifically utilized by bacterial pathogens without detriment to the host are novel concepts with great promise, potentially revolutionizing how infectious diseases may be treated in the coming century. Exposure to infectious microbes cannot be eliminated, particularly in developing countries and microbes cannot be stopped from evolving resistances to chemical agents. Thus, there is a need to continually evaluate and update the therapeutic arsenal to fight infectious disease and to improve methods for developing combinatorial chemical therapies that target multiple vulnerabilities of the bacterium and minimize microbial resistances.
Therapeutic drug development would benefit from animal infection models that are more flexible than those currently available. Chemical agents that either kill pathogens or halt their growth, traditionally have been identified using in vitro screens. After identification of a candidate compound, animal model systems may then be used to study their effect on the pathogen. There is a continuing need to conduct chemical screens in a convenient, inexpensive in vivo system that will better facilitate testing of novel anti-infective agents and formulating combinatorial therapies.
SUMMARY OF THE INVENTION
In vivo systems for screening and developing chemotherapeutics that disrupt microbial colonization of a host are described herein. The in vivo systems described herein can aid government, academic and biotech researchers in the development of both anti-infectives and drugs that directly target the microbe-host interaction, thereby minimizing the selective pressure that may lead to resistance to traditional chemotherapeutics, such as anti-infectives, antibiotics and antiviral drugs.
BRIEF DESCRIPTION OF THE DRAWINGS
The embodiments disclosed herein will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings. These drawings depict only typical embodiments, which will be described with additional specificity and detail through use of the accompanying drawings in which:
FIG. 1 is a graph demonstrating colonization by ETEC, showing the average colony forming units (CFU) per nematode exposed to the indicated rifampin-resistant bacterial strains on nematode growth medium (NGM) and colonization factor agar (CFA) for 24 hours. Values represent the means of three replicate assays, and error bars indicate 1 standard deviation (SD).
FIGS. 2A-2L comprise fluorescence microscopy images of ETEC bacteria within a nematode gut. After synchronization, LA nematodes were subjected to infection by ETEC and control strain MG1655 containing the GFP-producing plasmid pKH91 on NGM agar or CFA supplemented with appropriate antibiotics. After 24 hours, bacterial strains MG1655 (NGM: A, B; CFA: G, H), H10407 (NGM: C, D; CFA: I, J), and H10407P (NGM: E, F; CFA: K, L) were viewed by fluorescence and light microscopy. Light microscopy images (A, C, E, G, I, K) appear adjacent to fluorescent microscopy images (B, D, F, H, J, L). Arrows point to fluorescent bacteria. Representative images are presented. Magnification, ×200. Bars, 100 μm.
FIG. 3 is a graph demonstrating persistence of ETEC, showing the average CFU per nematode infected with the indicated bacterial strains on NGM agar. Twenty-four hours post-infection nematodes were transferred to rifampin sensitive MG1655 and harvested after 24 hrs (black bars) and 48 hrs (gray bars) of feeding. Values represent the means of three replicate assays, and error bars indicate 1 SD.
FIG. 4 is a graph demonstrating the effect of various compounds on bacterial colonization of the nematode gut. The graph shows the average CFU per nematode after they were exposed to the indicated rifampin-resistant bacteria strains. Nematodes were infected with prototypical ETEC H10407 or control MG1655 strains on NGM agar. After 24 hours of infection, 30 nematodes were harvested and placed in 1 mL M9 buffer (black bars), or M9 buffer supplemented with 100 μg/mL gentamicin (white bars), 50 μg/mL kanamycin (cross-hatched bars), 7 μg/mL heparin (checkered bars), or 0.01% mannose (speckled bars), and incubated at 26° C. for 24 hours. Values represent the means of three replicate assays, and error bars indicate 1 SD.
DETAILED DESCRIPTION
Those skilled in the art will recognize that the systems and methods disclosed can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In some cases, well-known structures, materials, or operations are not shown or described in detail. Furthermore, the described features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. It will also be readily understood that the components of the embodiments as generally described and illustrated in the Figures herein could be arranged and designed in a wide variety of different configurations.
In one embodiment of the present invention, an in vivo system may be used to screen and develop chemotherapeutics that disrupt pathogenic colonization of epithelial cell surfaces. Furthermore, embodiments of the present invention can aid government, academic and biotech researchers in the development of both anti-infectives and drugs that directly target the microbe-host interaction, thereby minimizing the selective pressure that may lead to resistance to traditional antibiotics and other chemotherapeutics.
In one embodiment, a C. elegans infection system may be used to screen for potentially therapeutic, chemotherapeutic agents against other pathogenic organisms that can colonize a C. elegans host. For example, one embodiment may be used to test the efficacy of a compound against bacterial, viral, and fungal organisms. More particularly, the C. elegans host may be infected with enteric bacteria, enteric viruses, and/or yeast and fungal species in order to test the effect of a candidate compound on the organism. Examples of enteric bacterial pathogens may include Salmonella spp., Campylobacter spp., E. coli, Shigella spp., Helicobacter pylori, Vibrio spp., Clostridium spp. and others. Examples of enteric viral pathogens can include hepatitis A virus (HAV), Norwalk-like virus (NLV), enterovirus (EV), rotavirus (RV), astrovirus (AV), and others.
In another embodiment, the infection system is amenable to developing specifically designed anti-infective compounds, e.g., chemicals that block and/or disrupt pathogen-host interactions. The C. elegans infection system can also be used to evaluate the in vivo activity of compounds that disrupt pathogen virulence gene regulatory processes, directly targeting the pathogen, or to screen libraries of compounds for their ability to limit pathogenic infections. Additionally, drug development and screening can be performed using wild type pathogens, making drug discovery more robust from the very beginning of the process. Toxicity problems associated with potential therapeutic chemicals may also be identified, as C. elegans , like humans, is a eukaryotic organism.
In yet another embodiment of the invention, manipulations can also be made to the nematode side of the C. elegans infection system because of the genetic tractability of C. elegans , i.e., ability to genetically manipulate this model organism. Even though C. elegans shares many protein homologues with humans, some receptors present on human cells to which bacterial antigens bind may be absent from the cells of the nematode. The desired human receptors can be expressed in nematodes in order to exploit specific microbe-host interactions for screening disrupting chemical agents. Because chemicals present in a liquid medium are taken into the nematode gut via pharyngeal pumping, our infection system can also be used for identifying chemical agents that disrupt viral pathogen adsorption to specific human receptor molecules.
The in vivo systems described herein include a model for use with the causative agent of traveler's diarrhea, also a common cause of childhood diarrhea in developing countries, enterotoxigenic E. coli (ETEC). There is a great need to develop effective, inexpensive therapies against ETEC to protect travelers visiting the developing world against this bacterium and to reduce its morbidity and mortality burden on children. ETEC bacteria colonizes the nematode gut in statistically higher numbers than a laboratory control strain of E. coli , and the simple C. elegans /ETEC infection system can be used to screen, and thus develop chemical agents that disrupt ETEC infection.
Referring to FIG. 1 , it was determined whether ETEC bacteria would be found in higher numbers within the nematode gut than the non-pathogenic, K-12 control strain MG1655. Age-synchronized L4 nematodes were placed on rifampin-containing NGM agar, a medium commonly used by researchers modeling bacterial infection in C. elegans , and CFA, a standard medium used to maximize expression of ETEC fimbriae, with pregrown lawns of rifampin-resistant bacteria as described previously. After 24 hours of incubation at 26° C. nematodes were harvested, washed, treated to kill bacteria external to the gut, pulverized and plated on selective media.
With continued reference to FIG. 1 , on NGM agar (black graph bars) the ETEC strains H10407 and H10407P lacking a virulence plasmid were found at a mean of ˜1×10 4 CFU per nematode and the number of MG1655 CFU per nematode was <10, a difference of at least three orders of magnitude. In contrast, on CFA medium (gray graph bars) H10407 and H10407P bacteria were found at a mean of ˜3×10 4 CFU per nematode, whereas the mean for control strain MG1655 was ˜4×10 3 CFU per nematode, a difference of approximately one order of magnitude. The difference between the ETEC strains H10407 and H10407P, and control MG1655 in their ability to colonize the nematode gut was statistically significant on both NGM and CFA media (NGM: P<0.001; CFA: P=0.006).
There was no significant difference in CFU per nematode values for wild type (wt) H10407 and the virulence plasmid lacking strain H10407P on either NGM or CFA agar. Because the H10407 and H10407P strains were able to colonize the nematode gut similarly, it may be concluded that factors in addition to the CFA/I fimbria, the CfaR regulator, or the ST toxin encoded on the H10407 virulence plasmid contributed to this phenotype.
Referring to FIGS. 2A-2L , the ability of ETEC bacteria to colonize the nematode gut by fluorescence microscopy was observed. Consistent with values obtained by standard plate count assays, GFP-labeled wt H10407 bacteria 24 hours post-infection were observed on both NGM and CFA and ( FIGS. 2D and 2J , respectively). In contrast to ETEC strain H10407, there was no colonization of the nematode gut by the control strain MG1655 on either NGM or CFA agar ( FIGS. 2B and 2H ). GFP-labeled ETEC strain H10407P were propagated on NGM and CFA within the nematode gut and observed by fluorescence microscopy ( FIGS. 2F and 2L ), but not as consistently as for the wt strain H10407 ( FIGS. 2D and 2J ).
As shown in FIG. 3 , prior to assessing feasibility of using the C. elegans model to screen for potential chemotherapeutic agents, it was investigated whether ETEC bacteria persist within the nematode gut. Nematodes were infected with rifampin-resistant ETEC or control bacteria. After 24 hours at 26° C. they were washed and placed on non-selective media containing the rifampin-sensitive strain MG1655. Twenty-four and 48 hours after the shift, the standard plate count assay was performed as described herein. At the 24-hour time point, rifampin-resistant strains H10407 and H10407P were found to be 2×10 4 and 5×10 3 CFU per nematode, respectively, whereas CFU per nematode for strain MG1655 was <10 CFU per nematode. Comparison of recoverable ETEC CPU per nematode versus that of MG1655 was significant (H10407: P<0.001; H10407P: P<0.001) ( FIG. 3 ). At the 48-hour point, all strains tested showed increased numbers within the nematode gut compared to the 24-hour time point and the values were: 5×10 4 , 2×10 4 and 2×10 3 for strains H10407, H10407P and MG1655, respectively. Again, the values for strain H10407 and H10407P were significantly different than that of strain MG1655 (P=0.001; P=0.025, respectively). As shown by FIG. 3 , ETEC bacteria persist within the nematode gut at least 48 hours after shift onto NGM agar containing a non-pathogenic, laboratory strain of E. coli.
In one embodiment, a C. elegans /ETEC infection system can be used to screen for chemotherapeutic agents able to disrupt colonization of the nematode gut. In another embodiment, a C. elegans /ETEC infection system may be used to test a range of compounds including, for purposes of example only, the bacteriocidal antibiotic gentamicin, bacteriostatic antibiotic kanamycin, heparin, which may disrupt bacterial adherence, and mannose, which inhibits type I fimbria-mediated adherence to host cells. Age-synchronized L4 nematodes were placed on NGM agar inoculated with either strain H10407 or the control MG1655. Twenty-four hours post-infection, 30 nematodes fed each strain were placed in M9 buffer or M9 buffer supplemented with the desired compounds. After an additional 24 hours of incubation at 26° C., nematodes were harvested, washed to remove exterior bacteria, pulverized and plated on selective LB agar.
As shown in FIG. 4 , incubation of ETEC infected nematodes with gentamicin resulted in a significant (P=0.004) reduction in the number of bacteria recoverable from the nematode gut. The mean numbers of nematodes recoverable after incubation in M9 buffer versus M9 buffer supplemented with gentamicin were 1×10 5 and 1×10 4 , respectively, approximately one order of magnitude. With continued reference to FIG. 4 , there was no significant difference in the number of recoverable ETEC bacteria after treatment with any of the other compounds tested. Additionally, gentamicin reduced the number of enteropathogenic E. coli (EPEC) strain E2348/69 bacteria recoverable from the nematode gut by approximately one order of magnitude compared to those recovered from the untreated EPEC-infected nematodes (data not shown). In contrast, treatment of the control strain MG1655 with gentamicin, kanamycin, heparin and mannose resulted in significant reduction in the number of bacteria recovered from the nematode gut (P<0.001 for all compounds tested). The present invention therefore also includes a C. elegans small animal infection model for studying EPEC. Accordingly, a C. elegans infection system could be used to screen for potentially therapeutic chemical agents against multiple E. coli pathotypes.
Materials and Methods
Bacterial and Nematode Strains, Plasmids and Growth Media.
The bacterial and nematode strains, and plasmids used for this study are listed in Table 1. Spontaneous rifampin-resistant mutants of the E. coli strains were isolated to limit contamination and prevent growth of the E. coli feeding strain OP50 in colonization assays. C. elegans strain DH26 fer-15(b26)II was obtained, which is sterile at 25° C. ( Caenorhabditis Genetic Center) to ensure a constant number of nematodes during the assays due to their inability to reproduce when incubated at 26° C. Nematodes were propagated on pre-grown lawns of the E. coli food strain OP50 at 15° C. prior to synchronization for the assays described below.
TABLE 1
Bacterial and nematode strains, and plasmids.
Strain or plasmid
Genotype or description
E. coli
H10407
wt ETEC serotype O78:H11
H10407P
H10407 lacking the CFA/I-ST plasmid
MG1655
F-λ −
OP50
Uracil auxotrophy
C. elegans
DH26
fer-15(b26(II) Sterile at 25° C
Plasmids
pKH91
ori15A gfpuv bla Ap R tet Tc R
Assays were performed on both nematode growth medium (NGM) agar (3 g NaCl, 2.5 g peptone, and 17 g agar to 1 liter in H 2 O; after autoclaving, add 1 ml 1 M CaCl 2 , 1 ml 1M MgSO 4 , 1 ml 2-mg/ml uracil, 1 ml 5-mg/ml cholesterol in ethanol, and 25 ml 1 M KPO 4 ) and colonization factor agar (CFA) (10 g peptone, 1.5 g yeast extract, 0.05 g MgSO 4 , 0.005 g MnCl 2 , and 20 g agar in 1 liter H 2 O) supplemented with the following antibiotics where appropriate: rifampin at 100 μg/ml and tetracycline at 15 μg/ml. NGM agar was supplemented with uracil because E. coli OP50 is a uracil auxotroph.
Standard Plate Count and Persistence Assays.
Prior to the assays, nematodes were age synchronized by a bleaching procedure. Briefly, nematodes/embryos grown on E. coli strain OP50 at 15° C. were harvested by washing the seeded NGM agar plate with M9 buffer (3 g KH 2 PO 4 , 6 g Na 2 HPO 4 , 5 g NaCl, 1 ml 1 M MgSO 4 in 1 liter H 2 O), were placed into a microcentrifuge tube, and then washed three times with 1 ml M9 buffer after spinning for 10 seconds at 12,000 rpm. Nematodes/embryos were resuspended in 100 μM9 buffer and bleach treated by adding 350 μl 280 mM KOH and 50 μl bleach. Nematodes/embryos were agitated gently and mixed intermittently for 10 min. After a 10-second spin at 12,000 rpm, the supernatant was discarded, and embryos were washed twice more with 1 ml M9 buffer as described above. After a final spin, the embryos and dead nematodes were resuspended in 50 μl M9 buffer; the suspension was placed on NGM agar plates with the food strain OP50, without antibiotic selection, and incubated at 26° C.
After 3 days at 26° C., L4 nematodes were removed from feeding using a platinum wire and placed on rifampin-containing NGM agar plates with pre-grown ETEC and control strains that were incubated at 37° C. overnight. Prior to seeding of C. elegans , NGM and CFA agar plates were shifted to 26° C., the temperature where they remained for the duration of the assay. For the standard plate count assay, nematodes were fed on ETEC and control strains for 24 hours. Ten nematodes were then chilled in M9 buffer for 24 hours at 4° C. to loosen bacteria adherent to the nematode cuticle, washed three times in M9 buffer, treated with 100 μg/ml gentamicin at 37° C. for 1 hour to kill exterior bacteria, again washed three times with M9 buffer, treated with 50% chloroform saturated M9 buffer for 10 minutes, washed three times in M9 buffer containing 1% saponin and 1% Triton X-100, pulverized for 10 seconds using a sterile plastic pestle and a Ryobi hand-held cordless drill, and finally plated on LB agar containing rifampin.
For the persistence assay, nematodes were fed on rifampin-resistant ETEC and control strains for 24 h at 26° C., washed thrice with M9 buffer, then transferred to pre-grown lawns of non-resistant MG1655 for 24 h at 26° C. Subsequently, nematodes were harvested and treated as described in the standard plate count assay above. Standard plate count, and persistence data did not fit a Poisson model due to over dispersion, and thus were analyzed by negative binomial regression using Stata, version 7.0 (Stat Corp., College Station, Tex.).
Fluorescence Microscopy.
Synchronized L4 nematodes were subjected to infection by ETEC and MG1655 strains containing the green fluorescent protein (GFP)-producing plasmid pKH91 on NGM and CFA supplemented with rifampin and tetracycline at 26° C. Twenty-four hours after infection, nematodes were removed using a platinum wire and placed in 500 μl of M9 buffer. Immediately prior to microscopy, 500 μl of a saturated solution of chloroform in M9 buffer was added to the nematodes, and they were incubated at room temperature for 10 minutes to kill and remove any bacteria adherent to the exterior. Nematodes were washed six times in 1 ml M9 buffer, chilled, transferred to 1% agarose pads on glass microscope slides to control the rate of desiccation, and visualized using an Olympus BX60 microscope fitted with an Optronics Microfire digital camera (Optronics, Goleta, Calif.).
Screen to Evaluate Chemotherapeutic Agents Against ETEC Infection.
Age-synchronized nematodes were placed on rifampin-containing NGM agar plates with pre-grown ETEC or MG1655 strains that were previously incubated at 37° C. overnight. (Prior to seeding with C. elegans , NGM agar plates were shifted to 26° C.). Nematodes were infected with the E. coli by feeding them on ETEC and control strains for 24 h, after which ten nematodes were transferred into a microcentrifuge tube for treatment with 1 ml M9 buffer containing either gentamicin (100 μg/ml), kanamycin (50 μg/ml), heparin (7.14 mg/ml), β-defensin at 10 μg/ml, or mannose at 0.01%, or no additional compound as a negative control for 24 h at 26° C. After treatment the nematodes were washed with M9 buffer to remove the treatment compound, chilled on ice at 4° C. overnight to loosen bacteria adherent to the cuticle, and washed as described for the standard plate count and persistence assays described above.
While specific embodiments and applications of infection models have been illustrated and described, it is to be understood that the invention claimed hereinafter is not limited to the precise methods, configurations, and components disclosed. Various modifications, changes, and variations apparent to those of skill in the art may be made in the arrangement, operation, and details of the methods, devices, and systems disclosed.
References
1. Alegado, R. A., M. C. Campbell, W. C. Chen, S. S. Slutz, and M. W. Tan. 2003. Characterization of mediators of microbial virulence and innate immunity using the Caenorhabditis elegans host-pathogen model. Cell Microbiol 5:435-44.
2. Barrett, J. F. 2005. Can biotech deliver new antibiotics? Curr Opin Microbiol 8:498-503.
3. Blattner, F. R., G. Plunkett, 3rd, C. A. Bloch, N. T. Perna, V. Burland, M. Riley, J. Collado-Vides, J. D. Glasner, C. K. Rode, G. F. Mayhew, J. Gregor, N. W. Davis, H. A. Kirkpatrick, M. A. Goeden, D. J. Rose, B. Mau, and Y. Shao. 1997. The complete genome sequence of Escherichia coli K-12. Science 277:1453-74.
4. Brenner, S. 1974. The genetics of Caenorhabditis elegans . Genetics 77:71-94.
5. Dowell, S. F. 2004. Antimicrobial resistance: is it really that bad? Semin Pediatr Infect Dis 15:99-104.
6. Evans, D. G., D. J. Evans, Jr., and W. Tjoa. 1977. Hemagglutination of human group A erythrocytes by enterotoxigenic Escherichia coli isolated from adults with diarrhea: correlation with colonization factor. Infect Immun 18:330-7.
7. Evans, D. G., D. Y. Graham, and D. J. Evans, Jr. 1984. Administration of purified colonization factor antigens (CFA/I, CFA/II) of enterotoxigenic Escherichia coli to volunteers. Response to challenge with virulent enterotoxigenic Escherichia coli. Gastroenterology 87:934-40.
8. Evans, D. G., R. P. Silver, D. J. Evans, Jr., D. G. Chase, and S. L. Gorbach. 1975. Plasmid-controlled colonization factor associated with virulence in Escherichia coli enterotoxigenic for humans. Infect Immun 12:656-67.
9. Evans, D. J., Jr., and D. G. Evans. 1973. Three characteristics associated with enterotoxigenic Escherichia coli isolated from man. Infect Immun 8:322-8.
10. Galen, J. E., J. Nair, J. Y. Wang, S. S. Wasserman, M. K. Tanner, M. B. Sztein, and M. M. Levine. 1999. Optimization of plasmid maintenance in the attenuated live vector vaccine strain Salmonella typhi CVD 908-htrA. Infect Immun 67:6424-33.
11. Gauthier, A., M. L. Robertson, M. Lowden, J. A. Ibarra, J. L. Puente, and B. B. Finlay. 2005. Transcriptional inhibitor of virulence factors in enteropathogenic Escherichia coli . Antimicrob Agents Chemother 49:4101-9.
12. Hung, D. T., E. A. Shakhnovich, E. Pierson, and J. J. Mekalanos. 2005. Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization. Science 310:670-4.
13. Iredell, J., and J. Lipman. 2005. Antibiotic resistance in the intensive care unit: a primer in bacteriology. Anaesth Intensive Care 33:188-95.
14. Kim, D. H., R. Feinbaum, G. Alloing, F. E. Emerson, D. A. Garsin, H. Inoue, M. Tanaka-Hino, N. Hisamoto, K. Matsumoto, M. W. Tan, and F. M. Ausubel. 2002. A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297:623-6.
15. Knutton, S., J. Adu-Bobie, C. Bain, A. D. Phillips, G. Dougan, and G. Frankel. 1997. Down regulation of intimin expression during attaching and effacing enteropathogenic Escherichia coli adhesion. Infect Immun 65:1644-52.
16. Laws, T. R., S. A. Smith, M. P. Smith, S. V. Harding, T. P. Atkins, and R. W. Titball. 2005. The nematode Panagrellus redivivus is susceptible to killing by human pathogens at 37 degrees C. FEMS Microbiol Lett 250:77-83.
17. Livermore, D. M. 2004. The need for new antibiotics. Clin Microbiol Infect 10 Suppl 4:1-9.
18. Mellies, J. L., A. M. Barron, K. R. Haack, A. S. Korson, and D. A. Oldridge. 2006. The global regulator Ler is necessary for enteropathogenic Escherichia coli colonization of Caenorhabditis elegans . Infect Immun 74:64-72.
19. Nataro, J. P., and J. B. Kaper. 1998. Diarrheagenic Escherichia coli . Clin Microbiol Rev 11:142-201.
20. Nguyen, T. V., P. V. Le, C. H. Le, and A. Weintraub. 2005. Antibiotic resistance in diarrheagenic Escherichia coli and Shigella strains isolated from children in Hanoi, Vietnam. Antimicrob Agents Chemother 49:816-9.
21. Ogiernan, M. A., A. W. Paton, and J. C. Paton. 2000. Up-regulation of both intimin and eae-independent adherence of shiga toxigenic Escherichia coli O157 by ler and phenotypic impact of a naturally occurring ler mutation. Infect Immun 68:5344-53.
22. Parry, C. M. 1998. Untreatable infections?—The challenge of the 21st century. Southeast Asian J Trop Med Public Health 29:416-24.
23. Roberts, T. M., and S. Ward. 1982. Membrane flow during nematode spermiogenesis. J Cell Biol 92:113-20.
24. Salyers, A. A., and Whitt, Dixie D. 2005. The looming crisis of antibiotic availability, p. 116-129, in Revenge of the Microbes: how bacterial resistance is undermining the antibiotic miracle. ASM Press, Washington D.C.
25. Sifri, C. D., J. Begun, F. M. Ausubel, and S. B. Calderwood. 2003. Caenorhabditis elegans as a model host for Staphylococcus aureus pathogenesis. Infect Immun 71:2208-17.
26. Thomas, R., and T. Brooks. 2004. Common oligosaccharide moieties inhibit the adherence of typical and atypical respiratory pathogens. J Med Microbiol 53:833-40.
27. Ulrich, R. L. 2004. Quorum quenching: enzymatic disruption of N-acylhomoserine lactone-mediated bacterial communication in Burkholderia thailandensis . Appl Environ Microbiol 70:6173-80.
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The present invention relates to a small animal model useful in identifying novel therapies for treating pathogenic diseases. This flexible biotechnology tool is valuable for developing novel chemotherapeutics for a broad range of microbial pathogens.
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FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 4,5-diamino shikimic acid derivatives, especially for the preparation of ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate and its pharmaceutically acceptable addition salts from 4-amino-5-azido shikimic acid derivatives, especially from ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate.
BACKGROUND OF THE INVENTION
4,5-diamino shikimic acid derivatives, especially the ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate and its pharmaceutically acceptable addition salts are potent inhibitors of viral neuraminidase ( J. C. Rohloff et al., J.Org.Chem. 63, 1998, 4545-4550; WO 98/07685).
A reduction of ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate to ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate by a hydrogenation in the presence of a Raney nickel catalyst is known in the art (J. C. Rohloffet al, loc.cit.).
It was found that the “5-azido” starting compound from its prior synthesis always contains a small amount of the “2,5-diazido” compound formed by formal addition of hydrazoic acid to the double bond. In the course of the hydrogenation the azido group in 5-position is readily converted to the desired amino group, the transformation of the azido group in 2-position however is very slow. Accordingly a “2-azido-5-amino” intermediate is formed which was shown to be “Ames positive” and therefore suspicious of being mutagenic.
This intermediate cannot be satisfactorily removed with the common purification techniques. Also, the problem cannot be overcome by prolonging the hydrogenation time because the “cyclohexene double bond” becomes hydrogenated, too.
An object of the present invention is, therefore, to provide a process for the preparation of 4,5-diamino shikimic acid derivatives which does not encompass the difficulties known in the art; i.e. a process which allows easy access to the target product in an excellent quality.
DESCRIPTION OF THE INVENTION
It was found that reduction of 4-amino-5-azido shikimic acid derivatives with a phosphine in the presence of a carboxylic acid surprisingly achieved this object.
The present invention therefore relates to a process for the preparation of a 4,5-diamino shikimic acid derivative of formula
and a pharmaceutically acceptable addition salt thereof
wherein
R 1 is an optionally substituted alkyl group,
R 2 is an alkyl group and
R 3 and R 4 , independent of each other are H or an amino protecting group, with the proviso that not both R 3 and R 4 are H;
the process being characterized by the reduction of a 4-amino-5-azido-shikimic acid derivative of formula
with a phosphine in the presence of a carboxylic acid. R 1 , R 2 , R 3 and R 4 have the same meaning in formula II as in formula I. If necessary, the process includes a further transformation of the 4,5-diamino shikimic acid derivative into a pharmaceutically acceptable addition salt thereof.
The term alkyl in R 1 has the meaning of a straight chained or branched alkyl group of 1 to 20 C-atoms, expediently of 1 to 12 C-atoms. Examples of such alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert. butyl, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers and dodecyl and its isomers.
This R 1 alkyl group can be substituted with one or more substituents as defined in e.g. WO 98/07685. Suitable substituents are C 1-6 -alkyl (as defined above), C 1-6 -alkenyl, C 3-6 -cycloalkyl, hydroxy, C 1-6 -alkoxy, C 1-6 -alkoxycarbonyl, F, Cl, Br, and I. Preferred meaning for R 1 is 1-ethylpropyl.
R 2 is a straight chained or branched alkyl group of 1 to 12 C-atoms, expediently of 1 to 6 C-atoms as exemplified above.
The preferred meaning for R 2 is ethyl.
The term amino protecting group in R 3 and R 4 refers to any protecting group conventionally used and known in the art. They are described e.g. in “Protective Groups in Organic Chemistry”, Theodora W. Greene et al., John Wiley & Sons Inc., New York, 1991, p.315-385. Suitable amino protecting groups are also given in e.g. WO 98/07685.
Preferred amino protecting groups are alkanoyl groups, more preferably lower C 1-6 -alkanoyl such as hexanoyl, pentanoyl, butanoyl (butyryl), propanoyl (propionyl), ethanoyl (acetyl) and methanoyl (formyl). The preferred alkanoyl group, and therefore preferred meaning for R 4 , is acetyl. The preferred meaning for R 4 is H.
The 4-amino-5-azido-shikimic acid derivative of formula (II) as starting compounds of the present process of the invention are accessible as described in J. C. Rohloff et al., loc. cit. and in WO 98/07685.
The preferred 4-amino-5-azido-shikimic acid derivative of formula (II) is the ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate. Accordingly, the preferred 4,5-diamino shikimic acid derivative of formula (I) is the ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate and the corresponding salt, ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1).
The phosphine used can be defined by the formula
P(R 5 ) 3 III
wherein R 5 is alkyl.
R 5 expediently is a straight chained or branched C 1-8 alkyl group as defined above.
Phosphines which can suitably be used are trioctyl phosphine, triisobutyl phosphine, tri-n-butyl phosphine, and triethyl phosphine. The most preferred phosphine is tri-n-butyl phosphine.
Although the ratio of phospine to the 4-amino-5-azido-shikimic acid derivative of formula (II) is not critical to the production of the desired 4,5-diamino shikimic acid derivative of formula (I), the phosphine is preferably added in stoichiometric amounts or in a slight excess of up to 1.05 equivalents relating to the starting amount of the 4-amino-5-azido-shikimic acid derivative of formula (II). One of skill in the art may adjust to relative amounts of phosphine and the 4-amino-5-azido-shikimic acid derivative of formula (II) to optimize them for the particular reaction conditions used.
Typically, the reduction is performed in a polar protic solvent which forms the reaction medium. Any conventional polar protic solvent can be used, such as alcohols, preferably aqueous ethanol or aqueous tetrahydrofuran, most preferably aqueous ethanol. However, the choice of solvent is not critical to production of the desired 4,5-diamino shikimic acid derivative of formula (I), and one of skill would be able to perform the reduction in other solvents using general knowledge of the art.
The reaction temperature is another non-critical variable; for instance, the reduction performs satisfactorily at room temperature. The preferred reaction temperature mainly depends on the phosphine used but most preferably lies in the range of −20° C. to 30° C., with between 0 and 25° C. being particularly preferred.
It can be favorable to perform the reaction at two temperature levels, thereby having the lower temperature range given above for the addition of the phosphine and thereafter having a slightly higher temperature of up to room temperature to bring the reaction to completion.
Catalytic amounts of a carboxylic acid present during the reduction were found to suppress the ester hydrolysis which otherwise takes place to a small extent of some percent and thereby leads to an undesirable impurity. The term “carboxylic acid” refers to any compound having one or more free carboxylic acid groups. Preferably, the carboxylic acid is an aliphatic carboxylic acid, having from 2 to 8 carbon atoms, such as acetic acid, oxalic acid, propionic acid, malonic acid, butyric acid, succinic acid, maleic acid, fumaric acid, valeric acid, glutaric acid, caproic acid, adipic acid, heptanoic acid, and caprylic acid.
The carboxylic acid is preferably present in the reduction reaction in an amount which measurably reduces the quantity of ester hydrolysis products present after the reaction of a 4-amino-5-azido-shikimic acid derivative of formula (II) with a phosphine to produce the 4,5-diamino shikimic acid derivative of formula (I). More preferably, the carboxylic acid is added to the reaction in quantities from about 0.5 to about 5.0 mol % of the starting amount of the 4-amino-5-azido-shikimic acid derivative of formula (II). Most preferably, the carboxylic acid is added to the reaction in quantities from about 0.5 to about 3.0 mol % of the starting amount of the 4-amino-5-azido-shikimic acid derivative of formula (II). Particularly preferred is the addition of carboxylic acid to the reaction in an amount of about 1.0 mol % of the starting amount of the 4-amino-5-azido-shikimic acid derivative of formula (II).
Preferably, one of skill in the art will be able to adjust the amount of a particular carboxylic acid added to the reaction according to the number of free carboxylic acid groups and the pKa value of the particular acid. Higher pKa acids will be required in relatively larger amounts than lower pKa acids.
Expediently, acetic acid, usually in the form of glacial acetic acid, is added in catalytic quantities of 0.5 mol % to 3.0 mol % of the 4-amino-5-azido-shikimic acid derivative of formula (II).
Although the time allowed for the reaction is not critical, generally, the reduction reaction is complete after 3 to 6 hours.
Thereafter work up of the reaction mixture can happen by applying methods known to those skilled in the art. Expediently the reaction mixture is, preferably after stabilization with ≦5 mol % acetic acid, concentrated in vacuo.
Though the 4,5-diamino shikimic acid derivative can be isolated e.g. by evaporation and crystallization, it is preferably kept in e.g. an ethanolic solution and then further transformed into the pharmaceutically acceptable addition salt following the methods described in J. C. Rohloff et al., J.Org.Chem. 63, 1998, 4545-4550; WO 98/07685).
The term “pharmaceutically acceptable acid addition salts” embraces all conventionally used salts for pharmaceutical preparations, including salts with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
The salt formation is effected with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts.
Preferred pharmaceutically acceptable acid addition salt is the 1:1 salt with phosphoric acid which can be formed preferably in ethanolic solution at a temperature of −20° C. to 60° C.
The following examples shall illustrate the invention in more detail without limiting it.
1. Preparation of Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate
50.0 g (0.147 mol ) ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate were placed in a nitrogen purged 1000 ml glass reactor fitted with a mechanical stirrer, a condenser, and a 250 ml dropping funnel. 300 ml ethanol, 50 ml water and 0.09 g acetic acid were added. To the resulting clear solution 31.4 g (0.155 mol) tributylphosphine dissolved in 150 ml ethanol were continuously added at a temperature of 5° C. (+/−5° C.) over a period of 30-90 min. Under slight cooling of the jacket (˜3° C.) the reaction temperature was kept at this temperature. The feeder was rinsed with 20 ml ethanol. The clear reaction mixture was stirred for additional 90 min at 5° C. (+/−5° C.) under slight jacket cooling. Subsequently the temperature was raised within 30-60 min to 20-25° C. and the solution was stirred for another 3 h (nitrogen evolving).
After the reaction was finished (HPLC control) 0.18 g acetic acid were added to the clear solution. Then the mixture was concentrated under reduced pressure (300 to 50 mbar) at a maximum temperature of 60° C. and a maximum jacket temperature of 75° C. near to dryness. The oily residue (80-100 ml) was diluted with 160 ml ethanol, the resulting solution was then again concentrated following the method as mentioned above. The oily residue was dissolved in ethanol up to a volume of 250 ml. The water content of this solution was determined by K F (Karl Fischer) titration of being less than 1.0% wt. %. Yield: 44.4 g (97% area by HPLC) of the title product in ethanolic solution.
2. Preparation of Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1)
In a dry and nitrogen purged 1000 ml glass reactor fitted with a mechanical stirrer, a condenser, and a 500 ml dropping funnel 17.0 g ortho phosphoric acid (85% in water) were dissolved in 400 ml ethanol and the resulting clear solution was warmed to 50-55° C. Subsequently the 250 ml ethanolic solution obtained from example 1 and containing 0.147 mol of ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate were added under stirring. After fast addition (10-15 min) of two thirds (ca.160 ml) of the total volume of this solution the addition was stopped and the supersaturated clear solution was seeded with 0.2 g of previously obtained ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1). Immediately afterwards crystallization commenced. The resulting thick suspension was stirred for 45-60 min at 50-55° C. Then the remaining amine solution was slowly added (45-60 min) to the suspension at 50-55° C. The feeder was rinsed with 20 ml ethanol. Subsequently the thick suspension was continuously cooled to 12-20° C. in about 4 h (cooling speed=10° C./h). To complete the crystallization stirring was continued at 12-20° C. for additional 2±1 h. Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1) was isolated by pressure filtration (0.3 bar nitrogen overpressure, Dacron® filter cloth). The crystalline product was washed twice with 240 ml acetone and twice with 300 ml n-heptane at room temperature. Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1) was dried in vacuo (≈20 mbar) at a maximum temperature of 50° C. until constant weight.
Yield: 54-55 g (88-91%) of the title product in the form of colorless needles with an assay of 99 wt. % (sum of impurities <0.5 wt. %, single impurities ≦0.1 wt. %).
COMPARISON EXAMPLE 1
Preparation of Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (Hydrogenation with Ra-Ni)
100 g (0.295 mol) ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate were dissolved in 800 ml ethanol and placed in a 21 steel autoclave together with 34 g Raney Nickel (Degussa) in 200 ml ethanol. The autoclave was closed rinsed twice with nitrogen and then set under 2 bar hydrogen pressure. Hydrogenation took place at a temperature of 20-25° C. under mechanical stirring a 1000 rpm until, after all the starting material had reacted, also the content of the “2-azido-5-amino intermediate” was ≦0.01% area (GC measurement) which was about 5-8 h. However, it was found that due to this “overhydrogenation” the “cyclohexene double bond” became hydrogenated, too.
The content of the respective cyclohexane derivative accordingly was 3-6% area (GC measurement).
Work up was performed by addition of 52 ml Cyclopentene and 1 h subsequent stirring in a nitrogen atmosphere. The reaction mixture was then pressed through a pressure filter (2 bar N 2 overpressure). The residue in the reactor was was then diluted with 400 ml ethanol followed by pressure filtration. The combined filtrates (ca. 1250 ml) were concentrated to 500 ml solution and contained about 70-80 g of the title product.
COMPARISON EXAMPLE 2
Preparation of Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1)
In a dry and nitrogen purged 2000 ml glass reactor fitted with a mechanical stirrer, a condenser, and a 500 ml dropping funnel 33.0 g ortho phosphoric acid (85% in water) were dissolved in 1400 ml ethanol and the resulting clear solution was warmed to 50-55° C. Subsequently the 500 ml ethanolic solution obtained from comparison example 1 and containing about 224 mmol of ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate were added under stirring. After fast addition (10-15 min) of two thirds (ca.330 ml) of the total volume of this solution the addition was stopped and the supersaturated clear solution was seeded with 0.4 g of previously obtained ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1). Immediately afterwards crystallization commenced. The resulting thick suspension was stirred for 45-60 min at 50-55° C. Then the remaining amine solution was slowly added (45-60 min) to the suspension at 50-55° C. The feeder was rinsed with 20 ml ethanol. Subsequently the thick suspension was continuously cooled to −20° C. in about 6 to 7 h. To complete the crystallization stirring was continued at −20° C. Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1) was isolated by filtration and washed twice with 480 ml of acetone (room temperature). The crystalline product was resuspended in 2600 ml acetone for 3 h at 24° C. to 28° C., filtrated, washed twice with 400 ml acetone (room temperature) and twice with 600 ml n-heptane (room temperature). Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1) was dried in vacuo (≈20 mbar) at a temperature of 25°-28° C. until constant weight.
Yield: 73-90 g (80-85%) of the title product in the form of colorless needles with an assay of 99 wt. %. The content of the “overhydrogenated” cyclohexane derivative still was between 0.5 and 2.0 area % (GC measurement).
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A new process for the preparation of 4,5-diamino shikimic acid derivatives starting from 4-amino-5-azido shikimic acid derivatives is provided.
4,5-diamino shikimic acid derivatives and its pharmaceutically acceptable addition salts are potent inhibitors of viral neuraminidase.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation application of U.S. patent application Ser. No. 10/498,235, filed Jun. 10, 2004, which is a national stage entry of PCT/IL02/00807, filed Oct. 3, 2002, which claims the benefit of U.S. Provisional Patent Application No. 60/326,430 filed Oct. 3, 2001. These three applications are incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates to traction systems. More specifically the invention is in the field of personal carriage of disabled persons.
BACKGROUND OF THE INVENTION
[0003] Versatile traction systems that permit movement on various different terrains are required for a number of different purposes. A particular example is a wheelchair. In most wheelchairs the traction system consists of wheels (typically one main, large wheel and one auxiliary, small wheel on each side) and it permits to move the wheelchair over smooth horizontal surfaces of such floors or pavements. These traction systems are not suitable for passing obstacles such as steps and others, moving through staircases or moving over rough terrains. A versatile traction system has been described in PCT Publication WO 99/21740. In the system described in this publication, means are provided that can change at will the traction configuration for the purpose of increasing the trafficability and safety. A preferred use of the system described in this PCT publication is wheelchairs.
SUMMARY OF THE INVENTION
[0004] In accordance with the invention a new traction system for a vehicle is provided. The term “vehicle” usually refers to a platform that moves over a terrain through wheels or track. This includes self-powered vehicles, for example a sport utility vehicle (SUV) or a carriage without self-powering means. A wheelchair is one specific embodiment of the vehicle in accordance with the invention. As will be appreciated from the disclosure below, the traction system provided by the invention is suitable for a wide variety of vehicles such intended for travelling over different terrains.
[0005] The traction system provided by the invention is versatile in that it has a variety of different configurations. It has one configuration particularly suitable for travelling over a relatively smooth terrain, for example, in the case of a wheelchair over floors, pavements or roads. Other configurations are suitable for travelling over difficult terrains, for example, rough surfaces, e.g. a non-paved road, and obstacles. In the case of a wheelchair, for example, the traction system permits the wheelchair to ascend or descend through staircases.
[0006] In accordance with the invention, a traction system is provided which utilizes auxiliary rollers that can stretch a flexible traction belt from a substantially circular configuration, into which the traction belt is naturally biased, into other traction configurations, as will be described below.
[0007] By a first aspect of the invention there is provided a traction system for a vehicle that comprises:
[0008] a support frame defining a circular track belt support that is revolvable about an axis at its center, said axis being in a fixed position with respect to a chassis of the vehicle;
[0009] a flexible track belt; and
[0010] a track belt stretching assembly comprising one or more track belt stretching rollers;
[0011] said system having one traction configuration in which the flexible traction belt is held on said support track forming a substantially circular, wheel-like traction surface, said belt stretching assembly can change to a stretching state in which said rollers engage said belt and stretch it from its state in said one traction configuration to a stretched state to define one or more other traction configurations of the system.
[0012] Also provided by the invention, according to another of its aspects, is a vehicle comprising one or more, typically two, traction systems of the first aspect. One example of a vehicle in accordance with this aspect, is a wheelchair.
[0013] In accordance with one embodiment, the rollers of the traction system, typically small wheels, are held on distal ends of belt extension arms respectively, that are in turn attached at their proximal ends, typically in a pivotal manner, to the vehicle's chassis.
[0014] In accordance with another embodiment of the invention, the revolvable support frame comprises two coaxial support members with a gap between them, that together define said circular track belt support. The void space that extends radially from the axis to the lateral part of the gap defines a belt-stretching assembly-holding space and in said one traction configuration, the belt-stretching assembly is housed within said space.
[0015] In the latter embodiment, the belt has preferably a central projection or series of projections that extend into the gap securing the track belt from sliding off its support. The belt-extension rollers similarly consist of two cooperating coaxial wheels that have a gap between them and said projections or series of projections fit into the gap when said rollers engage the track belt in said one or more other traction configurations of the system.
[0016] Also provided by another aspect of the invention is a flexible track belt for use in the above traction system.
[0017] By one embodiment of this latter aspect, a flexible track belt is provided that forms a closed loop, said belt consisting of a plurality of connected belt elements each of which includes at least two stretchable components. Each of the belt elements is biased into a contracted state by said components in which all members together bias the belt to assume a circular shape. Said belt can be stretched, forming a succession of stretched states by first causing the stretching of one of the at least two of said stretchable components, while the others are still relatively relaxed and gradually, with further extension, causing other of said stretchable components to stretch.
[0018] In accordance with a preferred embodiment, all of said belt members are integrally formed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] In order to understand the invention and to see how it may be carried out in practice, a preferred embodiment will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:
[0020] FIG. 1A is a schematic illustration of a side view of an embodiment of a traction system of the invention with retracted chain-stretching arms;
[0021] FIG. 1B shows the traction system of FIG. 1A , in one traction configuration with the two belt-extension arms extending beyond the wheel's parameters;
[0022] FIG. 1C shows the traction system of FIG. 1A in another traction configuration with only one of the belt-extension arms extended;
[0023] FIG. 1D shows the traction system of FIG. 1A with one of the belt-extension arms in the configuration of FIG. 1C , passing over an obstacle.
[0024] FIG. 2 is a schematic illustration of a cross-section through line II-II in FIG. 1A .
[0025] FIG. 3A is a schematic illustration of a side view of an embodiment of the invention including an angle limiter fitted on the chassis.
[0026] FIG. 3B shows the embodiment of FIG. 5A with a belt-extension abutting the angle limiter.
[0027] FIG. 4A shows one contracted configuration of a traction system in accordance with an embodiment of the invention.
[0028] FIGS. 4B and 4C are, respectively, side elevation and isometric views of the traction system of FIG. 4A with the front wheel and the flexible track belt removed for better viewing of the track belt tensioning system.
[0029] FIGS. 4D-4G show a succession of different traction configurations of a traction system in accordance with another embodiment of the invention.
[0030] FIG. 5A is a schematic illustration of a portion of a flexible track belt according to an embodiment of the invention showing ring-like elements of which the belt is made.
[0031] FIG. 5B is a schematic illustration of a portion of the track belt of FIG. 5A in a stretched state.
[0032] FIG. 5C is a schematic illustration of a portion of a flexible track belt according to an embodiment of the invention showing elements of the kind shown in FIG. 5A with tracking soles filled thereto.
[0033] FIG. 5D is a schematic illustration of a portion of the track belt of FIG. 5D in a stretched state.
[0034] FIG. 6 is a schematic illustration of a side view of a portion of stretchable belt according to another embodiment of the invention.
[0035] FIG. 7 shows a traction belt in accordance with another embodiment of the invention seen here in isolation in its circular form.
[0036] FIGS. 8A-8D show a longitudinal cross-section through a portion of the track belt of FIG. 7 in an initial and a succession of stretched states.
[0037] FIGS. 9A and 9B show the traction system of the invention fitted onto a wheelchair, in two different traction configurations.
[0038] FIGS. 10A and 10B show the traction system of the invention fitted onto an SUV, in two different traction configurations.
[0039] FIGS. 11A and 11B show the traction system of the invention fitted onto a motor cycle, in two different traction configurations.
DETAILED DESCRIPTION OF THE INVENTION
[0040] A side view of a traction system according to an embodiment of the present invention is shown in a schematic manner in FIGS. 1A, 1B , 1 C and 1 D to which reference is now made. The traction system generally indicated by arrow 10 includes a large circular frame (to be referred to hereinbelow as “wheel”) 12 revolvable around an axle 13 . Fitted on the rim of wheel 12 is a flexible traction belt 14 . Two extendible belt-stretching arms 16 and 18 are disposed behind wheel 12 . The extension of arms 16 and 18 in the embodiment is through a telescopic hydraulic pressure-activated elongation arrangement. Each of the stretching arms 16 and 18 is pivotally connected at its upper end by means of pivots 17 and 18 , respectively to a portion 24 of a chassis of a vehicle (not shown). Each of the stretching arms 16 and 18 has a respective tension wheel 20 and 22 connected at its lower end. In the traction configuration seen in FIG. 1A , the traction belt 14 is tightly fitted around wheel 12 and has the wheels in a circular shape. This traction configuration is particularly suitable for moving over a smooth terrain.
[0041] In FIG. 1B the same system is shown with both stretching arms extended in length and angularly displaced one from the other, defining a traction configuration in which traction belt 14 stretches around the upper part of wheel 12 and arrow tension wheels 20 and 22 . This traction configuration, as will also be explained below, has improved maneuverability over rough terrains, such as for example, a non-paved surface, as compared to the traction configuration of FIG. 1A .
[0042] In FIG. 1C a different traction configuration is shown in which only one stretching arm 18 and the associated tension wheel 22 is extended, essentially horizontally with the wheel 22 being somewhat more elevated than in the configuration shown in FIG. 1B . In FIG. 1D the system with the same tracking configuration as in FIG. 1C is shown passing over an obstacle, such as a rock 24 , with the belt being deformed by the change in distribution of strains on traction belt 14 .
[0043] Reference is now being made to FIG. 2 giving a schematic cross-section made through lines II-II in FIG. 1 . It should be noted that the relative dimensions of the various components do not actually reflect those dimensions in real life and the changes that were made were for the purpose of ease of illustration. As can be seen, the circular frame consists of wheel 12 and a corresponding coaxial wheel 12 A. A gap 30 is formed between them with the space confined between the two wheels constituting a track belt extension assembly confined to space 32 .
[0044] As can also be seen, wheel 20 has a cooperating coaxial wheel 28 with a gap formed between them as well.
[0045] Traction belt 14 is formed with a longitudinal projection or a succession of projections 34 projecting into gap 30 . Projection 34 ensures that the belt does not slip off the wheels. As can be seen both in FIG. 1A and FIG. 2 , in this retracted configuration, the belt extension assembly is confined to space 32 .
[0046] Reference is now being made to FIG. 3A and 3B showing another embodiment of the invention, similar to that shown in FIGS. 1A-1D , with the addition of an angular limiters 80 and 82 intended to limit the angular displacement of the belt stretching arms. The traction configuration in FIGS. 3A and 3B correspond to those of FIG. 1A and FIG. 1B and the same reference numerals as those used in FIGS. 1A and 1B used herein as well to indicate the same components.
[0047] Reference is now being made to FIGS. 4A-4G showing a traction system in accordance with another embodiment of the invention in a variety of views and in different successive traction configuration.
[0048] Reference is first being made to FIG. 4A showing a traction system generally designated 100 with a traction belt support 101 that includes two cooperating and coaxial support wheels 102 with a gap between them. These two wheels 102 define between them a track belt stretching assembly confining space that houses a track belt extension assembly generally designated 104 , some components of which can be seen through the cut-out in wheel 102 and which will be explained further below. Fitted over track belt support 101 is a flexible and extendible track belt 106 that is tightly held over track belt support 101 . The entire traction system in the configuration shown in FIG. 4A revolves about a fixed axle 107 through the intermediary of bearings 108 .
[0049] Reference is now being made to FIGS. 4B and 4C which are respectively side elevation and isometric view of the traction system in the configuration shown in FIG. 4A with one of wheels 102 and with the track belt removed to permit better view of the components of the track belt stretching system 104 .
[0050] Stretching system 104 includes two pairs of track belt extension wheels, including wheels 110 , and wheels 112 , revolvably attached at respective ends of arms 114 and 116 . Arms 114 and 116 are each pivotally fixed at 118 and 120 , respectively, two respect pivot members 122 and 124 that are rigidly linked to axle 107 (the link not shown for ease of illustration).
[0051] System 104 also includes two hydraulic piston members 130 and 132 pivotally anchored at 134 and 136 to a member (not shown) which is rigidly linked to axle 107 . In this manner arms 114 and 116 as well as piston members 130 and 132 are indirectly anchored to the chassis of the vehicle (through axle 107 which is in fact a chassis extension).
[0052] Provided on each of arms 114 and 116 are a pair of auxiliary wheels 138 and 140 .
[0053] Piston members 130 and 132 are linked, in a pivotal manner, to levers 146 and 148 which are in turn pivotally linked at 150 and 152 to respective arms 114 and 116 . Thus, by extension of the piston, arms 114 and 116 are angularly displaced in the direction of arrows 160 and 162 , respectively, thereby stretching the track belt as will be shown below.
[0054] System 104 also includes a spring system generally designated 170 that includes a spring member 172 that provides a biasing force for retracting the arms 114 and 116 on the one hand and provides some resilience to the arms in their stretched position on the other hand.
[0055] A series of successive stretched configurations of the traction system 100 can be seen in FIGS. 4D-4G . In FIGS. 4F and 4G , the stretchable track belt has been included for clear illustration of the function. With reference made now to FIG. 4F , it can be seen that in this configuration the track belt is stretched defining a straight ground engaging section 180 . In this configuration, the vehicle is in fact supported by the main wheel 102 and by the track belt tensioning wheels 110 and 112 . In this configuration, auxiliary wheels 138 and 140 , serve to further stabilize the track belt in its position.
[0056] In the configuration of the traction system 100 which can be seen in FIG. 4G , the track belt is fully stretched and the surface support is now only through wheels 110 and 112 , with the vehicle being elevated above the ground as compared to the configuration in FIG. 4F .
[0057] As can be appreciated, support 101 may be engaged rotatably to a motor in order to propel the vehicle.
[0058] Reference is now being made to FIG. 5A , which is a schematic representation of a portion of a track belt 200 which includes a plurality of linked ring-like elements 202 . Each of these ring-like elements which is made from a flexible thermoplastic material 204 and includes an internal reinforcement element 208 . Thus when stretched, into the position shown in FIG. 5B , through the reinforcing element 208 , the integrity of the track belt is maintained.
[0059] Another embodiment of a track belt 210 can be seen in FIG. 5C . Similarly as in the embodiment of FIG. 5A , the track belt includes a plurality of integral belt elements 212 linked by members 214 , which serve both for ground engagement and for structure reinforcement. When extended, members 214 maintain the track belt integrity.
[0060] Another embodiment of a track belt is shown schematically in FIG. 6 . Here again, a portion of the belt only is seen and similarly as in the embodiment of FIGS. 5A and 5C , it includes a plurality of belt elements 222 including each an elongation limiter 224 .
[0061] A portion of the track belt 240 in accordance with another embodiment of the invention can be seen in FIG. 7 . In accordance with this embodiment, the track belt is formed integrally from a flexible elastic material. The track belt is formed with a plurality of repeating integrally formed units 242 . Each unit 242 includes a relatively rigid surface engaging member 244 , an opposite radial projection 246 which fits into the gap formed between two pairs of wheels 242 and two pairs of stretching wheels 110 and 112 (see FIGS. 4A-4G ). Each element includes also two linking elements including an outwardly undulated sheet 250 and oppositely a thinner and shorter sheet 252 . A third connecting element is sheet 254 that extends between adjacent projections 246 .
[0062] A side elevation of a portion of the track belt of FIG. 7 in various states including a contracted state shown in FIG. 8A and a succession of stretched states shown in FIGS. 8B-8D . As can be seen in FIG. 7 , to which reference is again made, in the contracted state, the track belt is biased into a circular shape. Upon stretching, the first element to be stretched is connecting element 252 , with the other connecting element 250 being relatively relaxed. Upon further stretching, element 250 is recruited into the stretching process.
[0063] In its contracted state, the track belt travels relatively smoothly over a smooth surface. In case of a rough surface, in which case the traction system is changed to the configuration of the kind shown in FIG. 4F or 4 G, the flanks of members 244 can firmly engage with ground elements, obstacles, stairs, etc.
[0064] A wheelchair, an SUV and a motor cycle, fitted with a traction system of the invention, each, in two traction configurations, can be seen in FIGS. 9A to 11 B.
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A traction system for a vehicle has a support frame that defines a circular track belt support that is revolvable about an axis at its center, a flexible track belt; and a track belt stretching assembly comprising one or more track belt stretching rollers. The system has one traction configuration in which the flexible traction belt is held on said support track forming a substantially circular, wheel-like traction surface, and can change to a stretching state in which said rollers engage said belt and stretch it from its state in said one traction configuration to a stretched state to define one or more other traction configurations of the system.
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BACKGROUND OF THE INVENTION
This invention relates to interrupted flight screw presses, and more particularly to the worm and collar arrangement used in such presses.
Screw presses generally include a cage with inlet and outlet at opposite ends, defining a pressing chamber through which a rotatable screw assembly extends.
Each worm includes an annular body with an integral helical flight which extends circumferentially around all or almost all of the body, such as a worm where the flight extends circumferentially about 340° around the body. The worms and flights are spaced axially by collars also mounted on the shaft, and some means is provided for resisting rotation of material within the chamber to cause axial flow of material from each worm to the next successive worm. Typically, breaker bars or lugs project inwardly toward the collars for this purpose.
The screw assembly comprises a series of axially spaced worms mounted on a shaft and the wear pattern varies as the internal pressure increases and the fluids contained within the pressed solids drains away. Frequently, only the worms in the heavy wear locations need be replaced after an extended running period.
In operation, the shaft is supported and driven from one end and lateral components of forces acting on the cantilever mounted screw assembly can cause wear on the outer surface of the worms. In an arrangement where a cantilevered shaft is driven from the feed end, the wear is especially pronounced on the last few worms of the screw assembly since that end of the assembly is subject to greater lateral deflection. In many presses the extremely high pressure generated near the discharge end of the screw press coupled with the higher friction from a compacted material from which most of the fluids have been drained causes more rapid erosion of the flights and bodies of the worms than in the feed and/or low pressure end of the screw press. When the screw press is used for expressing liquids from material containing abrasives, for example, sugar cane bagasse having particles of sand therein, the wear is still further accelerated.
To minimize wear on the worms, hard coating on the outer surface of the flights and bodies of the worms has been employed, particularly on the worms closest to the discharge end of the press. Also cage contractions have been provided (as in U.S. Pat. No. 3,093,605) to make it easier to obtain access to the screw assembly to replace worm parts. But, it is still necessary to withdraw the worms and collars over the end of the shaft in order to replace worn or damaged worms.
In presses used for the drying or dewatering of synthetic rubber materials, it is sometimes necessary to provide for pressure changes (increase or decrease) beyond the range available through adjustment of the press core. Also, some presses have a drive connection at the discharge end of the press, (as in U.S. Pat. No. 3,276,354), and the tendency is for heavier wear to occur in the region of the discharge. Thus, whether it is desirable to change a number of worms and/or collars, or only one or more near the discharge end, it is desirable to minimize down-time of the press for such changes.
Also, presses used in some applications where corrosive liquids or materials are involved are provided with stainless steel parts, for example, shafts, worms, and worm bodies, etc. If it is necessary to slide a stainless steel worm body along a stainless steel shaft, of any appreciable difference, there is a tendency for these parts to gall; therefore, it is advantageous to minimize the amount of negative longitudinal movement between these parts necessary for replacement of the worm bodies.
SUMMARY OF THE INVENTION
The present invention is directed to a mechanical screw press incorporating an improved pressing worm which is ideally suited for use particularly as the final discharge sections of the press, as well as at other locations on the screw shaft.
The improvement comprises a worm body longitudinally split into at least two pieces having cooperating sections of worm flight thereon, and cooperating axially extending flanges or ribs extending therefrom. Additionally, the collars on opposite sides of the improved worm body are provided with cooperating undercuts providing a ring-like extension to fit over the flanges on the worm bodies and to hold the pieces of the split worm body onto the shaft. In this way, the split worm body may be readily removed from the shaft by moving at least one of the adjoining collars axially away from the worm body, allowing the pieces to be moved free in a sideways motion. A new split worm can be placed on the shaft and the collars slipped back to close and hold the new worm. This eliminates the necessity to slide all the worms and collars the full length of the shaft and off, and reassemble to replace one or more worn worms.
Accordingly, it is an object of this invention to provide an improved worm body which is split such that it may be readily removed as two or more pieces from the shaft by moving the adjoining collars axially away from the worm bodies to release the pieces from retaining parts of the collars which hold the pieces in assembled relation around the shaft.
Other objects and advantages of the invention will be apparent from the following description, the accompanying drawings and the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side elevational view of a screw press with one half of the cage removed to expose the screw assembly and with the feed end shown in section;
FIG. 2 is an exploded view of a portion of the screw assembly showing an improved worm in accordance with the teachings of the invention; and
FIG. 3 is a view with the shaft shown in phantom lines and with the collars spaced axially away from one piece of the worm body.
DETAILED DESCRIPTION OF THE INVENTION
Referring to the drawings, and particularly to FIG. 1, the press 10 which is illustrated is a continuous duty, interrupted flight, screw type machine. The press generally comprises an inlet hopper 12 through which materials to be worked upon and treated are supplied, a pressing chamber 14, formed by outer cage structure 16, an outlet 18, and a screw assembly 20 extending through said chamber 14.
The cage 16 is comprised of two symmetrical halves or sections 22 (only one being illustrated), each of which is semicylindrical in shape so that the chamber 14 is generally cylindrical. The sections 22 may be clamped together by a series of tie bolts (not shown) which extend within the holes 24, or by some other means.
The screw assembly includes a shaft 30 mounted for rotation in the upstanding end wall 32 of the inlet end of the press 10, and driven rotatably from either end by conventional drive 34, which may include any suitable form of power together with a gear case or the like by which the desired rotation of the shaft is obtained. Mounted on the shaft 30 are a feed screw 36, which receives the material to be worked on between the flights thereof and carries the material into the main body of the pressing chamber 14, and a plurality of collar members 38 and worms 40.
The worms 40 are keyed or otherwise secured to shaft 30 for rotation with the shaft and collars 38 may also be keyed to shaft 30. All of the feed screws 36, the collars 38 and worms 40 will be held on shaft 30 by an end or retainer nut 42. The cage structure 16 shown is of constant diameter and has a discharge outlet 18 comprised of a stationary discharge ring 44 mounted on the discharge end of the press 10 and in surrounding relation to the last collar 38. The ring is preferably slidable axially to define a variable discharge orifice 48.
The collar members 38 and bodies 50 of the worms 40 cooperate with the interior walls of the cage structure 22 to provide a through annular passage, i.e., pressing chamber 14, for the material, with such passage varying in cross-sectional area at different locations. As the material is fed through the pressing chamber 14 it is compressed and worked between the outer surfaces of the collars 38 and worm bodies 50 and the interior walls of the cage 22. The flights 52 (which may be notched) take up the material and move it along the length of the pressing chamber 14. Stationary breaker lugs 54, which are attached to the inner wall of the cage 22, are provided between the worms to restrain rotation of the material with the collars 38, and to cooperate with the worm flights 52 to obtain a tearing, shearing and working action of the material and to cause it to move in an axial direction so that it is eventually discharged out orifice 48.
At least some of the collars 38, usually the last one or more, will be tapered, i.e., they will increase progressively in cross-section, so that a restricted pressing annulus is formed and the material is subjected to increasing pressure for purposes of extracting fluids from or working the material. For this reason, it is normally the last worm or several worms which are subjected to the greatest forces and consequential wear.
In accordance with the present invention and in order to make the worms readily replaceable, the bodies 50 of the worms 40 have been longitudinally split into several pieces 60 which have portions of the helical worm flight 52 thereon. As shown in FIG. 2, there are two pieces 60, although the worm body 50 could be split into more. The worm bodies 50 have ribs or flanges 62 extending axially therefrom which are engaged by axially extending ring-like retainers 64 formed by undercuts in the end of the collar 38 which engages the flanges 62 of the worms 40. The collars 38 can have undercuts 64 in either or both ends depending on how many split worms it will engage. Also the flanges and retainers may be tapered to facilitate their alignment and engagement.
When the pieces 60 are brought together on shaft 30, they will be held thereon by the retainers 64 which will overlie the flanges 62, effectively clamping the pieces 60 to the shaft 30. Keyways 66 are provided in at least one, preferably both, of the pieces 60 for keying them to shaft 30 for rotation therewith. End nut 42 will axially hold the collars 38 and worms 40 on the shaft 30.
It is not necessary that all of the worms be "split worms" since the worms closest to the inlet do not necessarily wear as fast. When it becomes necessary to replace a worn worm, the end nut can be removed and the collars 38 moved axially along the shaft 30 as necessary, then as shown in FIG. 2, the pieces of the worm body are pulled sideways from the shaft, replaced or repaired, and the collars are returned into engaging relationship with the worm body pieces.
In some installations it may be desirable to use a spacer collar or sleeve (not shown) which is split longitudinally, with its parts held together by suitable fastening means. This spacer collar can then be removed to provide space to move the collars 38 axially along the shaft 30 as necessary to release the split worms. Such a spacer collar normally would be located outside the pressing cage at either end.
While the form of apparatus herein described constitutes a preferred embodiment of this invention, it is to be understood that the invention is not limited to this precise form of apparatus, and that changes may be made therein without departing from the scope of the invention.
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An interrupted flight screw press is provided, especially in regions of heavier wear, with one or more longitudinal split worm bodies. The bodies have axially extending end flanges which hook underneath flanges of adjacent collars to hold the worm in place. One or both of the worm bodies are keyed or otherwise fastened to the shaft for driving. Relatively slight longitudinal movement of one or both adjacent collars will release the parts of the worm body for repair and/or replacement without disassembling the entire worm-collar-shaft assembly.
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STATEMENT OF GOVERNMENT INTEREST
The invention described herein may be manufactured and used by or for the Government of the United States of America for governmental purposes without the payment of any royalties thereon or therefor.
BACKGROUND OF THE INVENTION
The present invention relates to energy absorbing devices, and more particularly to energy absorbers for attenuating high accelerations such as are caused by aircraft or other vehicle crashes.
For greater protection of, and reduction of injuries sustained by, seated pilots and passengers in aircrat or other conveyances or vehicles during potentially survivable crash environments, a proper energy absorber should be installed between the seat and the body of the vehicle. Such a device must not transmit acceleration levels that are injurious to the subject. However, most energy absorbers currently available, such as commercially available shock absorbers, are designed to protect rigid payloads, not dynamic systems such as are humans, and so would not adequately protect a seated man from high impact loads such as those occurring during a potentially survivable crash. Such available devices stroke at a constant force level, producing a constant force over their stroke length.
SUMMARY OF THE INVENTION
Accordingly, it is the general purpose of the present invention to provide an energy absorber capable of attenuating acceleration loads.
Other objects of the present invention are to provide an energy absorber capable of attenuating high impact or acceleration loads on a dynamic system such as a person, effectively protecting such a system from high impact loads such as would occur during a potentially survivable crash of a vehicle in which the person is a passenger and reducing potential injury to him therefrom, and maintaining the person at a potentially survivable level.
A still further object of the present invention is to provide an energy absorber having a minimum stroke while creating a tolerable environment for a dynamic system such as a human.
Briefly, these and other objects of the present invention are accomplished by an energy absorber whose response to force applied thereto results in force levels transmitted to the protected mass or system, with respect to absorber displacement or stroke, comprising an initial high peak or impulse, followed by a low valley or notch, followed by a constant intermediate force level plateau. The peak-valley portion of the curve accelerates the man up to a maximum velocity change and the plateau value maintains him at a survivable level. The notch can be generated by a physical separation of load carrying material, or by a reduced strength material. Any conventional constant force level absorber can be used to generate the remaining plateau portion of the response curve. In one embodiment of the present invention, a conventional shock absorber in series with a rupturing diaphragm generates the peak-valley-plateau waveform. A conventional shock absorber is connected in series with a notched diaphragm between the user's seat and the aircraft or other vehicle body. The diaphragm shears at its notch upon experiencing the peak force. Following breaking of the diaphragm, the protected system and conventional absorber are allowed to move freely without extension or compression of the conventional absorber, forming the valley, until a stop or collar fixed to the conventional absorber is engaged by structure fixed to the vehicle body. When this stop is engaged by a ring fixed to the protected mass or system and slidably disposed on the conventional absorber, the absorber then is compressed or extended conventionally to form the intermediate level plateau of the force-displacement curve of the present invention. In an alternative embodiment, a spring acts against a retaining ring or clip which is forced out of position by the peak transmitted load, after which the spring is urged against a honeycomb which is thereby crushed, forming the notch or valley. After the honeycomb is crushed, a conventional energy absorbing device is actuated, providing the plateau portion of the curve.
Other objects, advantages and novel features of the invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings wherein:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is the force-displacement response curve of the invention;
FIG. 2 shows a schematic representation of an aircraft seat and a preferred embodiment of an energy absorber according to the invention installed therein;
FIG. 3 is a section of the apparatus of FIG. 2 taken along the line 3--3 and showing the energy absorber in greater detail in an enlarged view with a portion shown in a sectional view;
FIG. 4 is a section of the energy absorber of FIG. 3 taken along the line 4--4;
FIG. 5 shows a schematic representation of an aircraft seat and another preferred embodiment of an energy absorber according to the invention installed therein;
FIG. 6 is a section of the apparatus of FIG. 5 taken along the line 6--6 and showing the energy absorber in greater detail in an enlarged view with a portion shown in a sectional view; and
FIG. 7 is a section of the energy absorber taken along the line 7--7 of FIG. 6.
DESCRIPTION OF THE PREFERRED EMBODIMENT
It is desirable that, in order to provide a person with adequate protection from injury, the person should be kept at a survivable level with a low probability of injury. Where this is accomplished with an energy absorber, displacement of the absorber should be minimized, particularly where there is limited space available to accommodate such displacement. This minimization with protection can be accomplished by bringing the person to the survivable level quickly, and then maintaining him at that level.
Referring now to the drawings, wherein like reference characters designate like or corresponding parts throughout the several views, there is shown in FIG. 1 an empirically determined notched force-stroke or force-displacement profile for an energy absorber according to the present invention for which injury reduction capability is optimized. This waveform shows the amplitude of the force transmitted by the absorber to the mass or system protected by the absorber, versus the displacement or stroke of the absorber in response to experienced forces. This waveform comprises an initial high force level peak or spike A followed by a low force level valley or notch B which in turn is followed by a constant or nearly constant force level plateau C whose force level is intermediate those of the peak and notch. The purpose of this response is to maintain the person at a surviviable level, where the probability of spinal injury to the person, the most likely initial injury, is minimized at 5% or less. The peak A and valley B portion accelerates the person up to a maximum velocity change, and the plateau C maintains the person at a survivable level. The initial peak or spike A, because of the dynamic response of the person, quickly achieves the acceleration or force response level of the person desired for protection of the person and reduces the absorber stroke required to adequately protect the person. However, to prevent increasing the probability of spinal injury to an undesirable level, any subsequent forces applied to the person to maintain the desired level must be preceded by a low level notch or valley B. The notch B prevents the collective acceleration experienced by the person from exceeding the desired level; the initial input A accelerates the person, but before the acceleration becomes too great that input is removed. The subsequent plateau C maintains the person's acceleration level at the constant desired survivable value. The result is that the acceleration experienced by the person causes him to compress up to a given level which is maintained. For example, peak A can have a peak force level of 5500 pounds with 0.184 inch displacement, notch B can have a constant force level of 1000 pounds with an additional 1.0 inch displacement, and plateau C can have a constant force level of 4400 pounds. As another example, the peak force can be 8600 pounds, the notch force can be minimal, and the plateau force can be constant and 3688 pounds. This waveform should be optimized for the anticipated user weight, seat weight, and vehicle deceleration. For example, for the optimized waveform values for a man weight of 170 pounds, a seat weight of 115 pounds, and the vertical deceleration pulse associated with the 95th percentile survivable accident for rotary wing and light fixed wing aircraft, the initial force and displacement are zero, the peak is 8500 pounds force at 0.2 inches displacement, the valley is at 1000 pounds force through 0.7 inches total displacement, and the plateau is 4000 pounds force for any further displacement, to for example 25 inches total displacement. The vertical deceleration pulse associated with the 95th percentile survivable accident for rotary wing and light fixed wing aircraft can be obtained from Turnbow, J. W., Carroll, D. F., Haley, J. L., Jr., and Robertson, S. H. Crash Survival Design Guide, USAAVLABS Technical Report 70-22, AvSer 69-4, rev. August 1969 (N.T.I.S. Accession No. AD-695 648), p. 21-22. For further information see Phillips, N. S., Carr, R. W. and Scranton, R. S., A Statistical Investigation into the Development of Energy Absorber Design Criteria, Report NADC-CS-7122, Dec., 30, 1971 (N.T.I.S. Accession No. AD-749 333).
There is shown in FIGS. 2-4 an energy absorber 10 according to the present invention and operating according to the curve of FIG. 1, connected between the aircraft or other vehicle body or other structure 12 and the user's seat or chair 14 by mounts or brackets 16, 18 and 20. The connection of absorber 10 to the vehicle body 12 can be to the vehicle floor. Seat 14 is configured to slide, such as on rollers, up and down rails 22, such as is the case with an aircraft ejection seat. Absorber 10 includes a rigid diaphragm or plate 24 having a notch 26 and sandwiched between rigid circular rings 28 and 30 which are fastened thereto and to mount 20 by bolts 32 or by any other suitable means. Ring 30 is attached to the user's seat 14 by mount 20, and ring 28 is configured to slide over conventional absorber 34. Conventional absorber 34 includes a portion 35 configured to slide in conventional absorber 34. Mount 16 rigidly attached flange 40, attached to portion 35 of conventional absorber 34, to vehicle body 12. Mount 18, fastened to diaphragm 24 such as by bolts 36, rigidly connects diaphragm 24 to vehicle body 12. For most effective breaking, diaphragm 24 has a notch 26 preferably concentric with conventional absorber 34 and with rings 28 and 30 and is preferably closely spaced about rings 28 and 30. Conventional absorber 34 can for example be any single-stage extension -type conventional absorber having a square or trapezoidal shaped force/stroke response curve such as an automobile fluid-type shock absorber or the absorbing device disclosed in U.S. Pat. No. 3,369,634 to Bernard Mazelsky. Impact base or collar 38 can be a ring or plate or other member attached, such as by a bolt or other suitable means, to the end of absorber 34 opposite portion 35.
Initially, seat 14 is supported on and connected to body 12 by mount 20, ring 30, diaphragm 24 and mount 18, which limit or prevent relative movement of seat 14 with respect to body 12. At impact, the seat 14 inertial force passes through mounting bracket 20 and ring 30 into diaphragm 24. No load can now be transferred into conventional absorber 34 nor mount 16 because there is a space D between ring 28 and impact base or collar 38 attached to absorber 34. The breaking point of notch 26 of diaphragm 24 corresponds to the peak force of the first portion A of the curve of FIG. 1. Because both rings 28 and 30 are rigid, diaphragm 24 will shear cleanly at the reduced thickness of notch 26. For example, a diaphragm plate 24 of 2024 aluminum, 0.125 inches thick, with a scribed circular notch of approximately 0.060 inch thickness would cause an 8600 pound peak force. Once the diaphragm 24 has ruptured under peak load, the support provided by mount 18 and the diaphragm is removed. Between shearing of diaphragm 24 at notch 26 and contact of ring 28 with collar or impact base 38, there is no solid physical connection between body 12 and seat 14, resulting in a valley B, or period of low force versus absorber 10 stroke or displacement, following breaking of the diaphragm. Seat 14 then drop the distance D between ring 28 and impact base or collar 38, forming notch B, after which absorber 34 elongates to form plateau C. After impact base or collar 38 fixed to conventional absorber 34 contacts ring 28, normal operation of conventional absorber 34 ensues, producing the intermediate level plateau portion C of the curve of FIG. 1. The force, then applied to absorber 10, is transmitted through ring 28 into the energy absorber attachment 38 and through conventional absorber 34 into the upper support structure 16. With the space D between impact base 38 and ring 28, the notch B force is a minimum force. However, it may be desired to insert crushable material therein. For adjustment of the slope of the leading edge of peak A, diaphragm 24 can be flexible instead of rigid, so that the diaphragm distends appropriately under applied force before breaking, but still limits relative movement of seat 14 with respect to body 12.
There is shown in FIGS. 5-7 an alternative energy absorber 42 according to the present invention and operating according to the curve of FIG. 1, connected between the aircraft or other vehicle body 12 and the user's seat or chair 14. Absorber 42 includes a spring 44 contained within a casing 46 which can for example be cylindrical, and which provides the initial linear portion of, and determines the slope of the leading edge of, the initial spike or peak portion A of the curve of FIG. 1. Casing 46 is divided into two casing portions 48 and 50 initially separating a distance E by a clearance space. The external end of casing portion 48 abutting seat 14 is initially spaced from the corresponding proximate end of guide 56 by an equal distance E. Spring 44 disposed within casing 46 urges apart casing portion 48 and plunger 54 slidably disposed within casing portion 50. Support guide 56 located at the longitudinal axis of casing 46 keeps plunger 54 properly aligned with respect to casing 46, and keeps cylinder portion 48 properly aligned with respect to cylinder portion 50, during motion thereof. Casing portion 50 is provided with a plurality of holes or slots 58, for example four, to accommodate a retaining ring or clip 60, which can for example be a spring steel clip, which while in place limits or prevents movement of plunger 54 with respect to cylinder portion 50. For example, ring 60 can include lugs or ears, each configured to slidably fit in a slot 58. Ring 60 thus isolates spring 44 from honeycomb or other crushable material 62. Honeycomb or other crushable material 62 rests on and is supported by solid filler block 64, which also helps align support guide 56 in casing 46. Block 64 can rest on or be connected to casing portion 50 adjacent conventional absorber 66.
The initial force applied to absorber 42 causes casing portions 48 and 50 to compress spring 44. Also, piston 54 presses against ring 60, which deforms thereby. When the peak force of the spike is reached, plunger 54 forces retaining ring 60 out of slots 58 in casing portion 50 and the spring 44 force no longer acts through casing portion 50. Instead, spring 44 now imposes a force on honeycomb 62 which collapses and produces a constant force level for the notch section B of the force/displacement curve of FIG. 1. Honeycomb 62 crushes until the clearance space E has been taken up and flanges 68 and 70 of respective casing portions 48 and 50 touch. Attached to casing portion 50, such as by welding, bonding, bolting or any other conventional means, is a commercially available compression-type energy absorbing device 66 which is actuated and experiences sufficient imposed forces to stroke or compress after clearance space E has been taken up, and provides the plateau portion C of the curve of FIG. 1. Conventional absorber 66 can for example, be any single-stage compression-type conventional absorber having a square or trapezoidal shaped force/stroke response curve such as an automobile fluid-type shock absorber or the absorbing device disclosed in U.S. Pat. No. 3,369,634 to Bernard Mazelsky. Portion 67 of conventional absorber 66 is configured to slide in conventional absorber 66, and is attached to body 12. Thus, spring 42 and ring 60 provide the peak or spike A of FIG. 1, honeycomb 62 provides the notch or valley B, and conventional absorber 66 provides the intermediate level plateau C. A breakable diaphragm can be used in place of ring 60. Also, flange 68 can be provided with a lip configured to engage flange 70 to limit separation of casing portions 48 and 50, to prevent accidental disassembly of absorber 42. Such accidental disassembly could also be prevented by the weight of seat 14. In addition, spring 44 and plunger 54 could, if desired, be replaced with a single solid plunger fixed to casing portion 48 and configured to engage ring 60. Furthermore, casing 46 can have other shapes than cylindrical, and retaining ring or clip 60 need not be circular. In addition, other configurations than the one shown in FIGS. 6 and 7 for retaining ring or clip 60 can be used.
In summary, operation of the foregoing invention is as follows. The present invention operates according to the force-displacement curve shown in FIG. 1. For the embodiment of the present invention shown in FIGS. 2-4, when force is first applied to absorber 10, diaphragm 24 is loaded until it breaks at notch 26 when the predetermined peak force is reached, thereby forming peak portion A of the curve of FIG. 1. Thereafter, ring 28 fixed to the vehicle body 12 slides freely through distance D on conventional absorber 20, thereby forming the notch or valley B of the curve of FIG. 1, until it contacts impact base or collar 38 fixed to conventional absorber 34. Thereafter, conventional absorber 34 is directly connected between the user's seat 14 and the vehicle body 12, and operates conventionally to form the intermediate force level portion C of the curve of FIG. 1. For the embodiment of the invention shown in FIGS. 5-7, when absorber 42 experiences initial loading, spring 44 is compressed in casing 46 until retaining clip 60 is forced out of cutouts or holes 58 in casing 46 at peak A force, after which spring 44 crushes honeycomb 62, forming the notch portion B of the curve of FIG. 1. After honeycomb 62 has been crushed sufficiently to close clearance space E, conventional absorber 66 provides the plateau portion C of the curve of FIG. 1.
It should be understood that conventional absorbers 34 and 66 can be arranged with respect to the user's seat 14 and the vehicle or other conveyance body or fuselage 12 such that compression-type or extension-type conventional absorbers can be utilized in any embodiment of the present invention. Also, the notch portion B of the curve of FIG. 1 can be provided using open space, permitting the seat to move freely between shearing of a breakable member and operation of the conventional absorber, or using crushable material, depending on the type, duration, and force level desired for the notch. Also, the present invention can be utilized in other conveyances than aircraft, such as racing cars, automobiles, or ships. In addition, any device capable of firm connection releasable at a predetermined force level can be used in place of diaphragm 24 or clip 60. Notch B can be generated by a physical separation of load carrying material or by reduced strength material.
Thus, there has been provided novel energy absorbing apparatus. The present invention deforms according to a force-displacement curve for optimal protection of the user from excessive forces of high impacts. The invention effectively protects human beings from high level input accelerations, such as occur during potentially survivable aircraft crashes. In particular, the probability of spinal injury to the user is substantially reduced.
Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims the invention may be practiced otherwise than as specifically described.
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A notched-energy absorber for attenuating high level accelerations such asould occur during aircraft crashes, thereby avoiding injury to a user. The energy absorber force-displacement curve has a large initial spike, followed by a valley or "notch" and then by a constant force level intermediate the spike and valley levels. In one embodiment, a conventional square-response type shock absorber is connected between a vehicle seat and the vehicle body by a shearable diaphragm fixed to vehicle structure. The diaphragm shears at a notch when it experiences an initial high force, after which the conventional absorber moves freely without deforming until it encounters a stop. The conventional absorber then elongates or compresses in a conventional manner. In an alternative embodiment, a spring is connected between the seat and the vehicle body. Initially, the spring is compressed by experienced forces until at a predetermined force level it forces out a retaining clip or ring. The spring thereupon crushes a honeycomb, forming the valley or "notch." After the honeycomb is crushed, a conventional shock absorber attached thereto is compressed in a conventional manner.
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[0001] The present application is a continuation in part of U.S. patent application Ser. No. 09/504,131, which is a continuation of U.S. patent application Ser. No. 09/280,312. U.S. patent application Ser. No. 09/280,312 issued as U.S. Pat. No. 6,051,016 on Apr. 18, 2002.
FIELD OF THE INVENTION
[0002] The present invention is directed to surgical tourniquet controllers, and more particularly to surgical tourniquet controllers having spatially separated operator control interfaces and fluid pressure controllers to allow management of equipment and operators adjacent to the surgical field.
BACKGROUND
[0003] Surgical tourniquets are used to provide a bloodless field for surgical procedures involving the extremities of the human body. The tourniquets function by compressing an extremity sufficiently to collapse blood vessels in the area of the tourniquet, thus preventing the flow of blood past the tourniquet.
[0004] A tourniquet being used during surgery must be monitored by a trained operator, typically an anesthesiologist. The function of the anesthesiologist is not limited to monitoring the tourniquet, but may also involve the administration of anesthesia to a patient, as well as the monitoring of the patient vital signs during the procedure.
[0005] Typically, the position of an anesthesiologist during a surgical procedure is away from the surgical field. Although surgical tourniquets are typically used on extremities, the location of the anesthesiologist is adjacent to the head of the patient, as shown in FIG. 1. This location generally assists in the reduction of congestion in the surgical field.
[0006] Siting the location of the controller associated with the surgical tourniquet is determined by the necessity to minimize the amount of equipment located in the surgical field, while also minimizing the length of the tubing necessary to provide a supply of a pressure medium to the tourniquet cuff. Accordingly, the surgical tourniquet controller is generally located near the perimeter of the surgical field to limit the amount of tubing required between the controller and a surgical cuff or cuffs. Locating the controller adjacent to the surgical field, however, also may require that an operator approach the surgical field to operate the control interface of the controller.
[0007] Additionally, the proximity of the surgical tourniquet controller to the surgical field results in the size and configuration of the controller having an effect on procedures within the surgical field. Reducing the size of the controller may reduce the impact the physical proximity of the controller to the surgical field will have, however may also adversely affect the suitability of the operator controls, displays, or interface. Finally, the configuration of the controller itself may be an issue in ensuring cleanliness in the area proximate to the surgical field.
[0008] In addition to the surgical tourniquet controller being in the operating room when a surgical procedure using a surgical tourniquet is being performed, other electronic equipment will likely be present, such as EKG monitors, EEG monitors, breathing monitors, and automated intravenous injection equipment, including equipment being used to administer anesthesia. Much of this equipment needs to be monitored to ensure its proper functioning, typically by the anesthesiologist responsible for the administration of anesthesia. If this equipment is distributed throughout an operating environment, operator task loading may increase unless additional personnel are provided. Including additional personnel in the operating environment, however, may also increase congestion for other personnel in the environment.
[0009] Due to the sensitivity of the operating environment, the potential of stray radio frequency emissions adversely affecting other electronic equipment must be minimized. Excesses of cabling may also be also undesired, due to the added complexity of ensuring that the cabling is accurately routed and connected, due to cleanliness issues associated with the cabling, and due to potential impacts the cabling may have on the operating environment, such as the creation of trip hazards.
SUMMARY OF THE INVENTION
[0010] The present invention is a surgical tourniquet controller which receives operational parameters from a remote unit, allowing flow control components associated with controlling a surgical tourniquet to be located adjacent to with a surgical tourniquet in use, while allowing an operator of the tourniquet to operate the flow components from a remote location, such as at an anesthesiologist's position, thus reducing the involvement of the surgical tourniquet operator near the surgical field.
[0011] The present invention may be embodied in a surgical tourniquet controller having a flow control unit located adjacent to the surgical field, and a remote unit for providing an operator interface to the flow control unit. The flow control unit may include at least one pressure control valve for regulating the pressure in a surgical tourniquet attached to the flow controller via a channel allowing the transmission of a fluid (including gasses). The regulation of the pressure in the surgical tourniquet cuff may be accomplished by the valve opening to allow a higher pressure medium to be exposed to the fluid channel, thus allowing the higher pressure medium to enter the fluid channel, increasing the pressure in the fluid channel. As the fluid channel is connected to the pressure cuff, the pressure in the pressure cuff will increase. The lowering of the pressure in the pressure cuff may be accomplished in any of several fashions, including the provision of a constant bleed-down condition, the provision of an exhaust channel from a surgical tourniquet cuff to the environment controlled by an exhaust valve, or by providing a pressure medium recovery capability which recycles the pressure medium from a surgical tourniquet cuff to the source of the higher pressure medium.
[0012] The flow control unit may also include a communications interface capable of receiving data from the remote unit. The data may include information associated with an operating profile for a surgical tourniquet. Minimally, the profile may include only a set pressure, allowing control over the inflation of any pressure cuffs attached to the flow control unit to be carried out by an operator. The profile may include a duration as well as a set pressure. Other information may be integrated into the profile to allow higher automation of control of the surgical tourniquet, such as the provision of threshold pressures which cannot be exceeded without direct operator intervention, durations which can not be exceeded without direct operator intervention, maximum pressures and durations, and functionality for control of multiple pressure cuff surgical tourniquets, such as those used in conjunction with localized anesthesia within the surgical region.
[0013] The remote unit may include an interface to allow an operator to control the profile of the surgical tourniquet. The interface may merely allow the operator to provide a set pressure, or may allow for the entry of complex profile parameters and the display of surgical tourniquet operational conditions, such as present pressure, display of any thresholds or maximum values, display of any durations set or time remaining under a set duration, or any other capability built into the flow control unit or remote unit. Although the flow control unit and the remote unit are contemplated as two separate devices, functions associated with these devices may be disseminated across more than two physical devices. An example of such a distribution would be the provision of a flow control processor in a computer located remotely from the surgical environment, while the operator interface and flow control valving are distributed between two devices in the operating environment. Accordingly, the remote unit also includes a communications interface to allow information in the remote unit to be transferred to the flow control unit, whether directly or indirectly, such as through a distributed flow control processor.
[0014] A pressure sensor may also be included in the flow control unit, allowing determinations of present pressure to be made for control purposes. Such a sensor does not need to be physically integrated with the flow control unit, but merely needs to be able to sense the pressure in a continuous volume of the pressure medium which includes the surgical tourniquet pressure cuff.
[0015] The flow control processor converts desired profile conditions into control signals for flow controls associated with the flow control unit. The flow control processor may use the output of the pressure sensor as a feedback to profile performance, as well as may utilize information from other sensors as a means to control surgical tourniquet performance.
[0016] The surgical tourniquet controller may also be embodied in a system including a flow control means for controlling the flow of a pressure medium into and out of a surgical tourniquet, and a remote unit means. The remote unit means for identifying parameters associated with controlling the operation of the flow control means. The remote unit means is located remotely from the flow control means, and is communicably connected to the flow control means via a communications path.
[0017] Although the present invention may be embodied in a system having a single operator interface located remotely from the flow control unit (referred to herein as the “remote unit”), redundant operator interfaces may be provided to reduce the potential impact of the failure of a remote unit on an on-going surgical procedure. A redundant interface may be provided on the flow control unit such that in the event of a failure of a remote unit or communications path, an operator may still successfully control the surgical tourniquet from the flow control unit.
[0018] In a more complex embodiment of the present invention, the surgical tourniquet flow controller may be embodied in a system having a surgical tourniquet pressurization manifold The manifold may have at least one pressure supply port and at least one pressure control valve, allowing the pressure in a surgical tourniquet connected to the manifold to be varied. A flow control processor may be provided for controlling the at least one pressure control valve in accordance with a pressure profile. The pressure profile may be defined at least in part by a parameter defining an operating condition of a surgical tourniquet The parameter may be a duration, desired pressure, or maximum allowable pressure value. The flow control processor may also include a communications interface for receiving information entered into a remote unit or other operating interface.
[0019] The present invention may also be embodied in a method for controlling at least one surgical tourniquet pressure cuff. Such a method includes the steps of providing a flow control unit adjacent to a surgical tourniquet pressure cuff, providing an operator interface remote from said flow control unit, providing a communications path between the flow control unit and the remote unit, receiving at the remote unit desired pressure cuff pressure parameters from an operator, communicating the desired cuff pressure parameters from the remote unit to the flow control unit via the first communications path, and pressurizing the at least one surgical tourniquet pressure cuff in accordance with the desired cuff pressure parameters.
[0020] Other features and advantages of the invention will be apparent from the following description of the preferred embodiment, and from the claims. Accordingly, reference should be made to the claims themselves
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] [0021]FIG. 1 illustrates the layout of an operating room configured for use in an operation involving placement of a surgical tourniquet on a lower extremity of a patient, wherein a surgical tourniquet controller according to the present invention is implemented for controlling the surgical tourniquet.
[0022] [0022]FIG. 2 illustrates a notional operator interface for a surgical tourniquet controller having a remote operator interface unit.
[0023] [0023]FIG. 3 illustrates the components of an embodiment of the present invention utilizing a hardwired connection as a communications path.
[0024] [0024]FIG. 4 illustrates an embodiment of the present invention utilizing a power distribution circuit as a communications path between a flow control unit and a remote unit.
[0025] [0025]FIG. 5 illustrates an embodiment of the present invention utilizing both radio frequency transmissions between a flow control unit and a remote unit (and a hardwired communications path between the flow control unit and the remote unit.
[0026] [0026]FIG. 6 illustrates an embodiment of the present invention wherein a computer network is utilized as the communications path to allow integration of the surgical tourniquet into the operating environment, shown in FIG. 6 by the provision of an integrated ECG monitor/remote unit, as well as the provision of a remote data logger and remote anesthesiology monitoring station.
[0027] [0027]FIG. 7 illustrates the steps in a basic process for controlling a surgical tourniquet according to the present invention.
[0028] [0028]FIG. 8 illustrates an embodiment of the present invention wherein the flow control unit includes a pressure generation source to allow the use of a surgical tourniquet in conjunction with an operating table not originally configured for use with a surgical tourniquet.
DETAILED DESCRIPTION OF THE INVENTION
[0029] Referring particularly to FIG. 1, wherein like numerals represent like elements, there is shown a basic embodiment of a surgical tourniquet control system (hereafter “STCS”) embodying the present invention. A flow control unit 102 and a remote unit 104 are provided. The flow control unit 102 (hereafter “FCU”) may include flow control valves for controlling the pressure in a pressure cuff 106 . Control circuitry for operating the valves may also be located in the FCU 102 . The remote unit 104 provides an interface between an operator 102 of the surgical tourniquet control system and the flow control aspects of the system.
[0030] As shown in FIG. 1, the remote unit 104 may comprise a remote unit separate from the FCU 102 such that the remote unit 104 can be co-located with an anesthesiologist or other medical personnel 108 (hereafter referred to collectively as the “operator”). By providing the remote unit 104 at a location co-located with the operator 108 (such as when the anesthesiologist is the operator), the work load of the operator, when the operator is responsible for equipment or procedures beyond the surgical tourniquet, can be reduced by allowing the controls for the disparate equipment to be placed in a single location.
[0031] The remote unit 104 may include a graphical user interface 202 such as the one shown in FIG. 2. This interface illustrates some, but not all, of the indicators and controls that can be associated with monitoring and controlling the functionality of the FCU 102 . The particulars of the graphical user interface selected may depend on the possible functions that the STCS is capable of performing. For example, where a timer is implemented into the STCS, the graphical user interface may include a display 204 showing the time remaining until the timer times out. Where the STCS incorporates flow feedback, as discussed in Applicant's co-pending U.S. patent application Ser. No. 09/955,763, herein incorporated in its entirety by reference thereto, the display may incorporate displays 206 , 208 associated with flow conditions, such as whether flow is detected past a surgical tourniquet.
[0032] In a first embodiment, such as shown in FIG. 3, the FCU 102 and the remote unit 104 may be communicably connected through wires 302 which provide an electronic signal path between the units. The remote unit 104 itself may be configured to allow it to be mounted to an EKG display being used by an anesthesiologist, or may be configured as a standard rack-mountable component allowing incorporation of the remote unit 104 into a standard rack being used to house other components used in the surgical theater.
[0033] The remote unit 104 may incorporate an output display 204 to display parameters to an operator. The output display may be a small flat screen display. A flat screen display may incorporate an input device 306 such as touch sensing technology to allow interaction between an operator 108 and the output display 304 allowing the operator to select operational modes or values through interaction with the output display 304 . Such a touch screen generally senses the touch at a location using screen coordinates, such as a touch at a certain row and column of the display. Software associated with the graphical user interface may be used to correlate the touch position with a control icon being displayed at the time the touch was detected. Accordingly, the touch screen can be used in coordination with the output display 304 to present a variety of indicators and controls in a single unit. The remote unit may also be provided with data logging capabilities, or data output capabilities, such as a printer or writeable media device.
[0034] The remote unit 104 may be configured such that it may be attached to standard equipment pole, such as discussed in Applicant's U.S. Pat. No. 6,051,016, herein incorporated in its entirety by reference thereto. The FCU may be provided with a pressure generation capability integral or may rely on an external pressure source.
[0035] The FCU 102 and remote unit 104 may preferably be configured with a minimum of surface features, such that the unit can be readily cleaned and sterilized. Such a minimum of surface features can be accomplished by limiting the presence of mechanical controls such as toggle or slide switches on either unit. The use of a touch screen assists in this endeavor.
[0036] Potential communication paths available for communicating data and instructions between an FCU and a remote unit include hardwiring, radio frequency transmission, and modulated light transmissions. Each data communication path has benefits and disadvantages when used in the surgical operating environment.
[0037] The simplest and likely most reliable method of providing a communications path between the FCU and the remote unit is to provide an electrically conductive wire 302 or wires between the FCU 102 and the remote unit 104 . The electrically conductive path can be used to transmit modulated electrical signals from the FCU 102 to the remote unit 104 , and vice versa. Technologies for transmitting modulated electrical signals between the units are known in the art, and generally incorporate some form of interface 310 , 312 in each unit as shown in FIG. 3.
[0038] The use of a wired communications path may increase the amount of wiring present in the operating room, potentially causing trip hazards. Short circuits from frayed insulation, electronic noise emissions from inductance associated with current flow through the wires, and signal noise in transmitted signals (due to wiring lengths receiving stray emissions within the operating room) are other potential adverse consequences associated with the use of a hardwired communications path. Additionally, the cable used as the communications path must also be kept in a clean fashion, most likely in a sterile condition.
[0039] Where a wire path for communicably connecting the remote unit 104 to the FCU 102 is to be implemented, a power supply line for the controller may be bundled with the control wiring to limit the number of separate cables that must be present in the operating room. The generation of electronic noise from a hardwired communications path may be reduced by adequate shielding of the cable used as a communications path. The communications protocol used in the dedicated cable may be chosen for compatibility with other electronic equipment in the operating environment, such that the cable may function as a network bus to allow multiple pieces of equipment to monitor the communications over the dedicated cable.
[0040] Radio frequency (hereafter “RF”) transmissions may be used to alleviate concerns over the presence of additional wiring in the operating room. RF transmissions can be accomplished in the operating room environment using low power transmitters to minimize the potential for effects between the emitted signals and other equipment in the operating theater. The benefits of RF transmissions as a communications path between the remote unit 104 and the FCU 102 are principally that the communications path does not require either a direct line of sight between the remote unit 104 and the FCU 102 , nor hardwiring which may become a hazard in the operating theater.
[0041] RF transmitters, however, are direct sources of RF noise in the operating room, and can adversely effect other electronic equipment. Where combustible materials such as oxygen are in use, RF transmissions must be maintained at minimal levels, to avoid the creation of charge potentials in metal structures that could cause static discharge. These problems can be minimized by the use of low powered transmitters, sufficient to transmit over the short distances necessary between the remote unit 104 and the FCU 102 .
[0042] Modulated light communications paths may also be used to transmit information between the Remote unit and the FCU, such as using modulated infrared light emitters and light sensitive elements in the Remote unit and FCU. The use of such technology is known.
[0043] The use of modulated light, such as infrared transmission, may be limited to line of sight, such that a visual path must be maintained between the transmitter and the receiver. Visual paths may also be susceptible to transient placement of objects between the remote unit and the controller, such as personnel in the operating theater, resulting in disruption of the communications path between the remote unit 104 and the FCU 102 . Such infrared transmissions may also be limited in the data rate that can be achieved due to longer dwell times necessary for accurate reception of transmitted signals.
[0044] Alternately, modulated light can be transmitted using fiberoptic cables, creating a hardwired communications path using modulated light. Such a communications path has the advantage of not generating electronic emissions from the cabling, but retains the potential disadvantage of placing a cable in the operating environment.
[0045] In light of the above concerns, it is presently preferred that a hardwired communications path between the FCU 102 and the remote unit 104 be utilized. The hardwired path may be either a dedicated cable, or the use of a power cord where the communications signals between the FCU 102 and remote unit 104 can be imposed over the alternating current transmitted over the power cord.
[0046] As shown in FIG. 3, a hardwired communications path 314 may be provided between an FCU 102 communications interface 310 and a remote unit 104 communications interface 312 . A control processor 316 may be provided to interpret operational parameters entered by an operator 108 (not shown) into a pressure profile at which a surgical tourniquet pressure cuff 106 is to be operated.
[0047] An input device 306 may be provided with the remote unit 104 , such that an operator 108 (not shown) can indicate desired parameters. In a rudimentary form, the input device 306 merely needs to allow an operator 108 (not shown) to indicate a desired increase or decrease in a tourniquet pressure. The addition of an output display 304 to indicate operating conditions associated with the pressure cuff 106 allows the operator greater information upon which to base operating decisions. Incorporation of additional functionality into the FCU 102 or remote unit 104 , such as but not limited to, a timer, allows presentations of additional functional constraints remaining to be displayed to an operator. Additional functions are described in the copending applications and patent incorporated herein.
[0048] The FCU 102 may also incorporate a relief valve 318 to allow pressure in a pressure cuff 106 to be reduced when desired, as well as a pressure sensor 320 to provide an indication of the occlusion potential of a pressure cuff 106 connected to the FCU 102 . As occlusion of blood flow can be detected through dynamic monitoring of pressure in the pressure cuff 106 , a pressure sensor 320 is not mandatory, but is rather a significantly useful capability.
[0049] As most operating rooms use clean or filtered power, ensured by the provision of dedicated power filters/sources for the operating room, the imposition of the communications signal over a power cord may be used to reduce the number of cables in an operating environment. Power cord transmission can be implemented using available protocols, such as “HOMEPLUG”, promulgated by HomePlug Powerline Alliance, or through the use of a proprietary protocol. The use of power cord transmission may be limited where clean power is not provided in an operating room. In such a situation, noise in the transmitted AC current may limit the ability to clearly transmit signals from a controller to a Remote unit. Such noise may be present due to other electronic equipment utilizing the same power grid as a communications path, or from noise generated by electrical motors using the same power grid.
[0050] A surgical tourniquet controller utilizing such a communications path is shown in FIG. 4. The FCU 102 and the remote unit 104 are both connected to the operating room power distribution network 402 , such that communications between the FCU 102 and the remote unit 104 can be accomplished by multiplexing a signal coexistent with existing alternating or direct current. As shown in FIG. 4, additional devices may also be connected to the power network 402 , allowing information from equipment such as, but not limited to, ECG 404 , EKG 406 , and automated blood pressure monitoring equipment 408 to be used to provide feedback to the surgical tourniquet controller system.
[0051] As shown in FIG. 5, redundancies may be incorporated into the system to provide increased reliability. Multiple communications paths, such as an RF communications path 502 and a hardwired communications path 504 (such as using electrical signals or modulated light signals) may be provided such that loss of communications over one path does not prevent operation of a pressure cuff 106 from a remote unit 104 .
[0052] Additionally, a redundant operator input device and output display (not shown) may be provided for the FCU 102 , such that in the event of loss of communications over available communications paths, control of a pressure cuff 106 may be accomplished from the FCU 102 . Such a redundant input and output capability may be a limited capability sufficient only to provide a minimal functionality, or be fully capable of controlling all functionality associated with the surgical tourniquet controller system.
[0053] The present invention may also be embodied in the apparatus shown in FIG. 6, wherein the FCU 102 is communicably connected to a computer network 602 . A network access device connected 604 to the same computer network 602 is thus able to function as a remote unit 104 for the FCU 102 , as well as to concurrently carry out other functions in the operating environment, such as functioning as an ECG or EKG monitor. Alternately, a network access device 606 may be located remotely from the operating environment, and function as a data logger, such that the network access device monitors the pressures associated with a surgical procedure, as well as the operator inputs, and the displays presented to the operator. Such a data logging function may be used to monitor the performance of the surgical tourniquet controller, as well as to allow correlation of operator performance with patient conditions exhibited during a procedure.
[0054] The use of a computer network as the communications path may further allow the flow controller to integrated with other equipment in the operating environment. Such a function is described in co-pending application Ser. No. 09/955,763, which teaches the use of remote cardiac function monitoring, such as, but not limited to, automated blood pressure and respiration monitoring equipment as feedback for performance of a surgical tourniquet. Alternately, as described above, the integration into an operating environment network may allow improved dissemination of surgical tourniquet condition information to personnel dispersed throughout a surgical theater, as well as located remotely from the surgical theater, such as network device 608 .
[0055] As shown in FIG. 7, the present invention may also be embodied in a method for providing a surgical tourniquet, comprising the steps of providing a flow control unit 702 adjacent to the location of a surgical tourniquet being used, providing an operator interface 704 remote from the flow control unit, and providing a communications path 706 between the flow control unit and the operator interface. An operator may then enter 708 desired operating parameters for the surgical tourniquet into the operator interface. The desired parameters are communicated 710 from the operator interface to the flow control unit, where a surgical tourniquet connected to the flow control unit can be pressurized 712 in accordance with the parameters. The parameters may be transformed into a pressure profile based on the parameters, or the parameters themselves may comprise the operating instructions to the flow control unit, such as the minimalist increase/decrease model discussed above.
[0056] The method may further comprise the step of providing a second 714 or redundant communications path between the flow control unit and the operator interface, such that should communications over the first communications path be degraded or lost, the second communications path may be used to ensure that an operator may continue to use the operator interface to control the flow control unit and surgical tourniquet pressurization.
[0057] When a second communications path is incorporated, the method may include checking to determine whether communications over a first communications path are available, such as by conducting a periodic request to communicate between the flow control unit and the operator interface to ensure that the communications path is valid. It may be preferable to limit such requests to periods when the flow control unit or operator interface are turned on, such that a signal can be generated 718 to alert an operator that communications between the flow control unit and the Remote unit have been lost, or that one communications path is not allowing communications.
[0058] The path checking function may also be implemented where only one communications channel has been provided, however the response associated with a detected loss of communications would be limited to generating a signal to warn an operator of the lost communications. Where redundant communications paths are implemented, communications between the flow control unit and the operator interface can be switched to a correctly functioning path in response to the detected loss of communications. Additionally, a signal can be generated under such circumstances, and a further signal can be used if every communications path suffers a loss of communications.
[0059] As is evident from the above description of the apparatus embodying the present invention, the method can be expanded to incorporate features associated with the disclosures of the copending applications, such as the use of occlusion sensors, more complex flow control systems, and feedback from ancillary equipment such as, but not limited to ECG and EKG sensors, without departing from the spirit or essential attributes of the invention.
[0060] As shown in FIG. 8, an additional benefit, such as embodied in the implementation shown in FIG. 8, is the ability to use the separation between the flow control unit and the Remote unit to simplify retrofitting a surgical tourniquet system to operating tables not originally configured for use with surgical tourniquets. Such tables may lack a pressure source for generating pressure for inflating a surgical tourniquet. Such tables will likely, however, have some provision for providing AC power. By incorporating a pressure generator 802 , such as a small air compressor, into the flow control unit 804 , the flow control unit 804 may combine all functionality required for supporting a surgical tourniquet. Further, by using a remote unit 806 , accessibility requirements for the flow control unit are reduced, such that the flow control unit may be placed underneath the table, and thus out of the way with regard to the surgical field.
[0061] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes of the invention. Accordingly, reference should be made to the appended claims, rather than the foregoing specification, as indicating the scope of the invention.
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The present invention is a surgical tourniquet controller which receives operational parameters from a remote unit, allowing flow components associated with controlling a surgical tourniquet to be collocated with a surgical tourniquet in use, while allowing an operator of the tourniquet to operate the flow components from a remote location, such as at an anesthesiologists position, thus reducing the involvement of the surgical tourniquet operator from the surgical field.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a U.S. national stage application of international application Serial No.: PCT/US2008/009190, filed Jul. 30, 2008, which claims the benefit of priority to U.S. Provisional Patent Application Ser. No.: 60/962,573, filed Jul. 30, 2007.
This invention was made with U.S. Government Support under Contract No. HD050655 awarded by the National Institutes of Health. The U.S. Government has certain rights in the invention.
FIELD OF THE INVENTION
The present invention relates to the field of functional balance training , methods and devices using altered gravity and virtual reality.
BACKGROUND OF THE INVENTION
Balance control is the foundation of our ability to move and function independently. Various neurological diseases and injuries to the brain, spinal cord and other parts of the motor control system may lead to immobility loss of function and quality of life. With increasing age, the occurrence of clinical balance problems and the natural deterioration of balance function will increase the risk of balance loss and falls. In fact, falls are the leading cause of accidental death in the elderly population with over 11,000 deaths as a result of falls each year. Severe head injuries, hip and other fractures are common consequences of a fall that may lead to serious handicap. Every year some 350,000 hip fractures occur in the US of which more than 90 percent are the consequence of falls. Hip fractures are the leading fall-related injury that causes prolonged hospitalization and 25% of elderly persons who sustain a hip fracture die within six months of the injury. Hip fracture survivors experience a 10 to 15 percent decrease in life expectancy and a significant decline in overall quality of life. The scope of this problem is expected to grow as the number of elderly individuals will increase dramatically over the next 25 years.
Early mobilization following any injury or disease that leads to immobility is crucial for recovery and in the case of hip fractures, early ambulation has even been shown to be directly predictive of extended survival. Gait training using partial body weight support (BWS) is a neurorehabilitation technique that is becoming increasingly popular and is being used to enhance locomotor recovery following a range of motor disorders related to brain injury including stroke, spinal cord injury, cerebral palsy, Parkinson's disease as well as for early mobilization following total hip arthroplasty. However, improvement in balance function following BWS training only occurs in patients with minimal function prior to treatment suggesting that BWS training is not sufficiently challenging for more functional patients. Consequently, the challenge to the balance is either too small to stimulate improvement or is not sufficiently specific to balance function. Another issue associated with the BWS technique is that the harness supporting the subject decreases the need for natural automatic postural adjustments that are required for independent gait because the harness provides a lateral as well as vertical support. During gait the main site for an active control of balance is the step-to-step mediolateral placement of the foot. When supported by a harness the patient's mediolateral movement will be limited by a medially directed reaction force component that will help stabilize the body in the frontal plane and decrease or even eliminate the need for automatic postural adjustments that are required for independent gait. This restriction on automatic postural adjustments limits the full advantage of unloaded gait training.
Therefore, a need exists for a device that incorporates the principals of BWS but overcomes the problems associated with a harness that decreases the need for natural postural adjustments including mediolateral movements. There also exists a need for a device and method that provides unloaded gait training that allows automatic postural adjustments. There is also a need for a device and method that overcomes the aforementioned limitations that is completely mobile and therefore easily transportable into a patient's hospital room or placed in an outpatient clinic or in a patient's home, if necessary. The benefits of such a device would also extend to injured athletes to enhance their functional rehabilitation.
BRIEF SUMMARY OF THE INVENTION
The present invention overcomes the aforementioned problems by providing a device and method that allows a patient to incorporate natural automatic postural adjustments directly in the BWS training. We have discovered that upright balance function improves after training in a 90 degree tilted visual environment with the subject in a supine position strapped to a device that freely moves on air-bearings and a gravity-like load of preferred magnitude provided with a weight stack. For movements in the frontal plane, this tilted room environment requires the subject to perform associated postural adjustments as if in an upright environment. The foregoing is accomplished by providing a bed and exercise module including a modified hospital bed with an attachment for various exercise devices such as a treadmill, stepper, cycle or balance board; a virtual environment module that includes three-dimensional displays; a gravity force module that includes an open- or closed-loop control pneumatic force actuator system; a linear bearing assembly; and an air-bearing and support module including a light-weight mounting frame or harness with air bearings, back-pack harness and substantially flat surface plate. The device and method of the present invention may also be used for functional balance training for athletes, in-home gyms, and for gaming and entertainment purposes.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 schematic illustration of the device in accordance with the present invention.
FIG. 2 is a perspective view of the support frame and linear bearing attachment in accordance with the present invention.
FIG. 3 is a detailed view of the support frame, air bearings, and support surface in an alternative view of the present invention.
FIG. 4 is a top plan view of the back of the frame showing air bearing detail in accordance with the present invention.
FIG. 5 is a schematic view of the air bearing in accordance with the present invention.
FIG. 6 is a perspective detailed view of the back of the frame attached by a pulley system to the linear bearing in accordance with the present invention.
FIG. 7 is a side view showing detail of the linear bearing assembly.
FIG. 8 depicts pre- and post-training data of subjects' Maximum Voluntary Contraction strength (MVC) tested during a full body squat extension.
FIG. 9 depicts pre- and post-training results of the mediolateral critical time parameter, which indicates an improved ability to quickly correct and control balance tested in an upright position with respect to gravity.
FIG. 10 is an illustration of the present invention adapted to be used with Body Weight Support techniques.
DETAILED DESCRIPTION OF THE INVENTION
Referring to FIG. 1 , the device 10 in accordance with the present invention includes a support and exercise module including a wheel-frame of a standard hospital bed 12 with, in addition to a flat “floor” surface 15 , an attachment for various exercise devices such as a treadmill 14 , stepper, cycle or balance board; a virtual environment module 16 that includes one or more three-dimensional displays; a gravity force module that includes an open- or closed-loop control pneumatic or other force actuator system 18 ; an air-bearing and support module 20 including a light-weight frame 28 with a harness 32 or other attachment system such as Velcro and the like-, air bearings 34 thereon and a substantially flat surface plate 30 or other system to provide minimal friction movement; and a linear bearing assembly 67 . The virtual environment may optionally include a graphics computer 16 with a head mounted display (not shown) and a multi-camera still-image acquisition system.
Patient Support and Exercise Module
Referring to FIG. 1 , a standard hospital bed 12 may be modified for the proposed system. The bed 12 includes a welded, one-piece steel frame that supports up to 750 pounds with an optional multi-function electric operation to adjust head, feet and high-low position. Modifications include attaching mounts for the additional system modules including the virtual environment 16 , G-force 18 and air-bearing and support 20 modules. In addition, the foot rest end of the bed 12 is reinforced with an aluminum platform holding attachment mechanisms for the different exercise devices that can be connected to the system. These exercise devices may include a mini-stepper, a balance board, a cycle ergometer, a treadmill, and other similar devices known to those skilled in the art. Two longitudinal support bars may optionally be mounted above the bed to allow elastic and/or non-elastic cords providing constant-force support against gravity through an active or passive mechanism to be attached to each limb as required under conditions when the patient requires assistance during gait and other exercise. Alternatively, the support and exercise module may optionally be a simple table or substantially flat surface that is connected to a set of adjustable legs having wheels. The table or modified bed is constructed to support subjects of varying weights and includes a flat non-friction surface plate 28 . As depicted in FIG. 1 the subject wears a back-pack-like frame 28 that includes air-bearings 34 allowing low-friction mediolateral motion. The “room” contains common physical objects that have a visual “polarity” with respect to the direction of gravity. The patient is viewing at least one optional automultiscopic display 16 that shows three-dimensional images. The display shows a window 26 in a virtual room that surrounds the patient. Images of the patient's own home, office, or other familiar environment can also be shown. In an alternative embodiment, one or more walls can surround the table or modified bed to effect a “room”-like environment with objects having visual polarity placed in the room as described hereinafter.
Virtual Environment Module
A class of disorientation illusions occur in most individuals when placed in a 90 or 180 degrees tilted room that contains “polarized” objects meaning that they are familiar to the subject and that they have tops and bottoms that align with our common perception of vertical in relation to the direction of gravity, for example tables, chairs, cups on tables etc. In this environment some 90% of subjects experienced the illusion of being upright with respect to gravity illustrating that the perception of upright is heavily dominated by vision. Therefore, the design of the inventive system includes a virtual environment module for balance training and may include for example, at least one wall 24 or a plurality of walls that simulate a room built over the bed module. The room may include a window 26 , a door, a wall-clock, a table with a table cloth, a wastebasket with some trash and framed pictures on the walls and other such desirable objects, which may be fastened in place to help convey the illusion to the subject of a vertical orientation, in other words “standing upright.” In yet a further alternative embodiment, and as described in detail below, the patient may view an automultiscopic display 16 that shows three-dimensional images, such as images of the patient's own home, office, or other familiar environment. Similar images can be displayed through a stereoscopic head-mounted display that provides an immersed 3D environment. While in a supine position on the bed, patients perceive they are standing in the room while attached to a lightweight frame 28 that is in operable communication with and thereby connected to the surface plate 30 as described in detail below.
Referring to FIGS. 2-4 , the light weight frame 28 includes a harness 32 into which a patient is strapped. The frame 28 and harness 32 comprise a modified back-pack. The frame 28 includes friction-free air-bearings 34 . A source of compressed air 35 feeds the air-bearings 34 via tubing 38 allowing the patient to move freely in the frontal plane, similar to when in upright standing. As best seen in FIGS. 2 , 3 and 8 the light weight frame 28 is attached to a cable 62 that runs through a pulley system 76 , 78 , 90 , 92 which is operably connected to a linear bearing 40 and to the pressure controlled pneumatic linear force actuator 19 which is capable of being set to provide different levels of a gravity-like force to the cable 62 that the subject must balance against to remain “upright.” The cable 62 transmits the force to the frame 28 and thereby to the subject who while attached to the frame 28 must resist the force. The cable-frame attachment 60 is near the level of the lower lumbar back of the subject, the approximate location of the center of gravity along the longitudinal body axis when standing, and at the mediolateral midline of the body. The system is structured such that cable 62 runs between the legs of the subject. The linear bearing 40 allows near friction-free side to side motion thereby nulling out any mediolateral force vectors that are generated when the subject moves from side to side. This ensures that the gravity-like force is perpendicular to the support surface of the system, just like the direction of real gravity is perpendicular to the level ground. Although standing balance must be maintained the subject cannot fall to the ground thus providing a safe environment for functional balance training tasks.
In a further alternative embodiment, the Virtual Environment Module may include a multi-camera still-image display for balance training using three-dimensional automultiscopic displays. Visual cues to convey a perception of being in an upright environment are provided through state of the art display techniques with 3-D images of a virtual environment. Typically, stereoscopic 3-D displays require polarized or shutter glasses to deliver the projected images separately to each eye. Inconvenience, often discomfort, and, in the case of shutter glasses, cost, are some of the reasons that eyewear-based 3-D displays are far from practical. Additionally, stereoscopic systems render 3-D environment from one single viewpoint thus making any viewer movement in front of the screen unnatural (static 3-D objects rotate with lateral head motion). Automultiscopic displays require no glasses and project multiple views; a viewer can clearly experience depth and even see a little around objects. These displays are capable of projecting several, typically nine (based on nine different images), views of a 3-D scene. The present invention may optionally use two- and three-dimensional virtual reality systems having displays that can be placed in front of the subject and/or on the side, or both in front and the side, or so called Head Mount Displays worn by the subject. Still images displayed on these screens represent virtual “Windows” to an outside environment or show other surrounding environment and thereby promote a visually induced reorientation illusion where subjects perceive themselves as being upright with respect to gravity.
G-Force Module
The G-Force Module includes a pressure controlled pneumatic linear force actuator system 18 , which includes a compressor 35 , a pneumatic linear actuator 18 , an electro-pneumatic pressure control valve (not shown) and a motion control PCI board (not shown). In an alternative embodiment, the linear force actuator may comprise a simple weight stack so long as it is capable of exerting a pseudo-gravitational force on the subject. The pneumatic actuator may be of “sure-fit” kind meaning that it has NFPA (National Fluid Power Association) industry-standard mounting footprint to ensure easy interchangeability with the ability to handle high forces. The bore diameter is 2 ½ to provide up to ˜300 lbs of force at 50 psi air pressure for the proposed model actuator. Compressed air is provided from the on-board air compressor 35 or through a wall outlet commonly available in hospital treatment rooms as in the case in which the present invention is being used to rehabilitate a patient. The actuator is double acting, i.e. it has two compressed air ports. The first extends in the “push” direction and serves to supply compressed air to the air bearings 34 . The second retracts in the “pull” direction which exerts force via cable 62 on the subject through frame 28 worn by the subject. The actuator allows constant pressure (force) control by using an electro-pneumatic pressure control valve, known to those skilled in the art. The pressure-control valve converts an electrical signal proportionally into pneumatic pressure allowing for closed-loop control of pneumatic pressure or force electronically. The proposed valve has an integral pressure sensor for closed-loop control allows a flow rate of over 28 SCFM, output pressure up to 150 psi, and a hysteresis of less than one psi. The motion control PCI card will be mounted in the PC that will be running servo tuning and analysis software for proportional control of the force module. The PCI card and software package supports advanced PID compensation with velocity and acceleration if needed for an improved control of the force module.
In yet a further alternative embodiment an open-loop air pressure control system may be employed. The open-loop control system includes the foregoing air compressor and a control valve system but further includes an air tank 37 connected in series with the pneumatic actuator 18 . Those skilled in the art will appreciate that in this alternative embodiment the force output of the actuator is passively regulated. The open-loop control system with the added air tank provides a substantially larger volume than the closed-loop control system alone and better “absorbs” fluctuations in applied G-force level during movements by the subject. A given change in position of the piston in the air cylinder due to vertical subject movements will be “diluted” across the larger volume when the tank is present and G-force fluctuations will therefore be smaller. As a result, the subject is exposed to a more constant load as set with the control valve.
Air-Bearing Support Frame Module
Referring to FIGS. 2-6 a light-weight frame 28 including harness 32 that is wearable by and attached to a subject. Light-weight materials from which the frame 28 may be constructed include aluminum, plastic, titanium and the like. The frame 28 may comprise a modified back-pack. Referring to FIGS. 5-6 the frame 28 includes at least one air bearing 34 that allows the subject frictionless movement in the frontal plane. In an alternative embodiment, a plurality of air bearings 34 may be used. The bearing or bearings 34 include a porous face 42 and are approximately 2½ in diameter and support approximately 175 lbs each at 60 psi with 10 micron lift. The porous air bearings 34 , typically made from carbon, provide an almost uniform air pressure across the entire bearing surface. The carbon surface 42 also provides greater bearing protection if there is an air supply failure, allows the bearings to be moved during air failure without damaging the support surface, and results in a stiff, stable crash tolerant bearing. The bearings 34 include a threaded stud 44 having first and second ends 52 , 54 . First end 52 provides the connection to frame 28 . Second end 54 is operably connected to a ball joint 56 that is received by a ball joint depression 58 that moveably and rotatably seats the ball joint 56 allowing the bearing face 42 to become parallel with the support surface 30 . The threaded stud 44 is operably connected via a lock nut 48 to the frame 28 Those of ordinary skill in the art will appreciate that the porous air bearings described above can be modified in known ways to attach to frame 28 without destroying functionality. The support surface 30 may be stainless steel, granite or any other hard flat surface known to those skilled in the art. The present invention includes three air bearings 34 operably connected to the frame 28 and placed in each corner of an isosceles triangle with its base perpendicular to the subject's long body axis and placed at the lower lumbar level and its vertex angle on the cervical region of the spinal column. This geometrical arrangement provides good stability and distribution of load as well as optimal contact with the flat support surface The air bearings 34 are operably connected to the compressor 35 of pressure controlled pneumatic linear force actuator system 18 via a series of tubing 38 . Tubing 38 may be rigid or flexible and can be made of any material that allows connectability with the air bearings. The frame 28 is operably connected to cable 62 via a connecting element, such as cable eye 60 secured with a nut as best seen in FIG. 4 . Cable 62 in connected via a pulley system to a linear bearing and to pressure controlled pneumatic linear force actuator system 18 that simulates a pseudo-gravitational force on the patient as hereinafter described. The linear bearing 40 nulls out mediolateral forces generated when the subject moves thereby permitting natural postural adjustments and unrestricted mediolateral movement to occur within the range of the linear bearing system described below.
Linear Bearing Assembly
Referring to FIG. 7 , the linear bearing assembly 67 in accordance with the present invention is shown. The linear bearing assembly includes linear bearing 40 including a C-shaped in cross-section linear guide block 82 and linear rail 71 having top and bottom grooves 84 , 85 along the length thereof. The top and bottom C-portions of linear guide block 82 include bearings therewithin 86 which travel in grooves 84 , 85 . Housing 70 is operably connected to linear bearing 40 . Housing 70 includes two opposing faces 72 , 74 that support first and second pulleys 76 , 78 and form channel 80 on the backside. Cable 62 attached to frame 28 feeds through first pulley 76 , through channel 80 , and through second pulley 78 , feeds horizontally underneath the full length of the top surface 30 through a third pulley 90 (best seen in FIG. 1 ) located below the top surface 30 near subject's head level and then feeds vertically downward to a level just above the hospital bed wheels to a fourth pulley 92 . Cable 62 then operationally connects to the linear force actuator 19 . Those of ordinary skill in the art will appreciate that any number of pulleys can be used in the system so long as cable 62 travels over a long distance. The use of a long travel for the cable helps decrease angular deviations during mediolateral body movement and sway in addition to the use of a linear bearing to null out remaining forces. When the patient commences training, for example walking on a treadmill, linear bearing 40 allows the patient to make unrestricted, automatic postural adjustments such as mediolateral movement due to the sliding motion of housing 70 attached to linear guide block 82 along linear rail 71 .
In yet a further embodiment of the system in accordance with the present invention the system can be adapted for use with BWS systems when the subject is in a standing position and upright with respect to gravity, as best seen in FIG. 10 . The subject wears support frame 28 and harness 32 which is connected via a means of weight support 95 to cable 96 . Alternatively, cable 96 can be directly attached to support frame 28 . Cable 96 is operably connected to a linear bearing 40 which travels on linear rail 71 . Cable 96 can be directly attached to linear bearing 40 or can be threaded through a housing with pulleys as described above. Rail 71 is supported by structural frame 100 constructed to attach to or surround treadmill 97 or other exercise tool. Alternatively structural frame 100 can be affixed to the floor. When the subject commences walking on treadmill 97 , he or she is able to make automatic postural adjustments such as mediolateral movement due to the sliding motion of linear bearing 40 along linear rail 71 , thus overcoming the problems of mediolateral support forces associated with BWS techniques. In the forgoing open-loop system, a lateral force will pull the linear guide block to a neutral position thereby nulling out the lateral force. In the forgoing open-loop system, a lateral force will pull the linear guide block to a neutral position thereby nulling out the lateral force. In an alternative embodiment, a closed-loop system includes a sensor that detects the lateral force or angle deviation away from the pseudo gravity line. An “error signal” activates a motor operably connected to the system that actively moves the linear bearing to a position where the lateral force or angular deviation is zero.
EXAMPLES
Two groups of healthy subjects; 1) Strength and Balance Training (hereinafter “S&B,” consisting of 6 female and 6 male, 20-21 yrs, 170.1±9.2 cm, 68.6±10.8 kg individuals) and; 2) Strength Training (hereinafter “S,” consisting of 5 female and 6 male, 19-25 yrs, 173.5±9.0 cm , 68.7±10.8 kg individuals) participated in the study. The S&B group performed “squats” in a tilted room environment, on a balance board that required them to balance in the mediolateral direction, whereas the S group performed squats without balance requirement (sliding on fixed rails and no balance board). The strength program was progressive (50%-75% of 1 RM) and each session consisted of 6 sets of 10 repetitions.
The following measures were conducted before and after training; 1) Maximal Voluntary Contraction (MVC) during an isokinetic squat extension (10 deg/s & 35 deg/s) using a computerized exercise system (CES, Ariel Dynamics, CA, USA); 2) Stationary stance on one leg with eyes open and with eyes closed while standing on a force platform. Ten trials of 30s standing were performed under each condition. Subjects rested between as needed between trials to minimize effects of fatigue. Subjects were instructed to stand as still as possible during each trial and to actively minimize their perceived body sway. Center of pressure (COP) data were recorded at 100 Hz. Summary statistics and Stabilogram-Diffusion parameters were extracted from the COP data.
FIG. 8 shows maximum isokinetic strength before and after training in the tilted environment for the two groups. Both the S&B and the S groups showed statistically significant improvements in MVC during both isokinetic velocities. Several subjects in the S&B group reported subjectively that they perceived improvement in their ability to control posture following the training. Measures of balance control confirmed such an improvement. Overall, effects on postural parameters were mainly seen in the mediolateral direction, specific to the direction of postural challenge in the tilted room during training.
FIG. 9 shows the mediolateral critical time parameter for eyes-closed conditions from the Stabilogram-Diffusion analysis. This parameter indicates the time interval at which, on average, the random walk behavior of the COP changes from being predominantly persistent (tendency to continue moving in the same direction) to being predominantly antipersistent (tendency to reverse direction). The critical time parameter was 105 ms shorter after training for the S&B group (p<0.05,) with a non-significant decrease of 9 ms in the S group. A similar, although non-significant, decrease was seen with eyes open in the S&B group (p<0.14).
The combined S&B training appeared to alter the relationship between balance performances under eyes closed vs. eyes open (Romberg ratio). The
Critical Displacement parameter, indicating the average COP displacement at which the postural control process becomes mainly antipersistent, was five times higher under eyes closed compared to eyes open pre-training for the S&B group and decreased by 30% to 3.5 post-training (p<0.04). There was a small non-significant decrease in the S group (6%). A post-training decrease in the S&B group of 21% (p<0.03) was seen for the ratio between mediolateral short-term diffusion coefficients indicating a relatively lower short-term stochastic activity under eyes closed conditions as a result of the training. This was mainly related to a 40% increase in mediolateral short-term stochastic activity under open eyes conditions (p<0.012). No change was observed for the S group.
The foregoing results support the view that combined strength and balance training in a tilted environment, where the vestibular tilt orientation mechanism cannot be used for balancing, can improve balance function during upright while balancing against gravity in addition to muscular strength. Thus patients undergoing rehabilitation can target postural control and may improve training efficiency by a multimodal regimen where strength training is performed under conditions where balance is challenged.
The present invention has been described with reference to several embodiments. The foregoing detailed description and examples have been given for clarity of understanding. No unnecessary limitations are to be understood therefrom. It will be apparent to those skilled in the art that many changes can be made in the embodiments described without departing from the scope of the invention. Thus, the scope of the invention is not intended to be limited to the structures described herein, but only the language of the claims and its equivalents.
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We present a tool that can enhance the concept of BWS training by allowing natural APAs to occur mediolaterally. While in a supine position in a 90 degree tilted environment built around a modified hospital bed, subjects wear a backpack frame that is freely moving on air-hearings, as a puck on an air hockey table, and attached through a cable to a pneumatic cylinder that provides a load that can be set to emulate various G-like loads. Veridical visual input is provided through two 3-D automultiscopic displays that allow glasses free 3-D vision representing a virtual surrounding environment that may be acquired from sites chosen by the patient. Two groups of 12 healthy subjects were exposed to either strength training alone or a combination of strength and balance training in such a tilted environment over a period of four weeks.
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BACKGROUND
[0001] This invention relates to machine-assisted exercising.
[0002] Exercising is frequently done with the help of an exercise machine that resists motion of the exerciser's arms or legs.
[0003] Some machines, such as rowing machines and cycling machines, resistive forces that are small enough to permit aerobic exercising over a longer period of, say, 20 to 40 minutes.
[0004] Other machines, such as weight machines, offer higher resistive forces for so-called resistance exercising that entails fewer repetitions.
[0005] Some exercise machines use wind drag created by a fan to provide the resistance.
SUMMARY
[0006] In general, in one aspect, the invention features an exercise machine in which a fan has a rotor that generates drag by causing air to move in response to exercising by a user. A deflection structure deflects air that the rotor has moved and is adjustable to control the amount of drag generated by the rotor.
[0007] Implementations of the invention may include one or more of the following features. The rotor moves and the deflection structure remains stationary. The deflection structure has deflection surfaces, e.g., curved vanes, at least one of which is adjustable relative to the path of air that the rotor has moved. Each of the deflection surfaces is independently rotatable from an open position to a closed position.
[0008] The deflection structure and the rotor are located at different positions along an axis of the rotor. An air directing surface is positioned to deflect air from the deflection structure toward the fan rotor. A closed housing surrounds the rotor and the deflection structure.
[0009] In general, in another aspect of the invention an outer dimension of the fan rotor and in inner dimension of the housing define a cylindrical chamber, and the fan rotor vanes direct air from inside the rotor to the cylindrical chamber and cause swirling of the air in the chamber.
[0010] In general, in another aspect, the invention features an exercise machine that has a fan that generates drag by causing air motion, a beam, a carriage, and a seat. The carriage rides back and forth along the beam and is coupled to drive the fan in response to force applied by a user exercising. The fan is driven when the carriage is riding in one direction along the beam and is undriven when the carriage is riding in the other direction along the beam. A seat is configured to be movable to different positions along the beam relative to the carriage and to different orientations relative to the carriage.
[0011] Among the advantages of the invention may be one or more of the following. The wind resistance provided by the fan may be adjusted to provide different exercise experiences. Different exercise modes may be achieved by rearranging the seat relative to the moving carriage, adjusting the seat angle, and adjusting the handle height. In the case of strength training, wind resistance eliminates the need for hundreds of pounds of weight. The force experienced by the user is determined by the user effort. This means the muscles can be appropriately stressed through the entire range of motion. With commonly used weight-lifting equipment, the muscles may be stressed at the proper level only at the place in the exercise motion where the muscles are the weakest.
[0012] Other advantages and features will become apparent from the following description and from the claims.
DESCRIPTION OF THE DRAWINGS
[0013] [0013]FIGS. 1 and 2 are top and side views, respectively, of an exercise machine.
[0014] [0014]FIG. 3 is a perspective view of an opened fan canister.
[0015] [0015]FIGS. 4 and 5 are a wire frame perspective view and an end view, respectively, of a fan rotor.
[0016] [0016]FIG. 6 is a partial end view of stator vanes.
[0017] [0017]FIG. 7 is a perspective view of a fan canister viewed from the lid end.
[0018] [0018]FIGS. 8 and 9 are schematic views of airflow inside the fan canister.
DESCRIPTION
[0019] As seen in FIGS. 1 and 2, in an exercise machine 10 , a wind-generating fan 12 imposes a selectable amount of resistive force as a carriage 14 is pushed or pulled along a beam 16 by a user (not shown).
[0020] The wind-generating fan 12 is driven by motion of the carriage through a system of chain loops and pulleys. One chain loop 20 connects a pulley 22 , which is mounted between the fan's axle 24 , to a larger pulley 26 , which is mounted on a pair of brackets 27 (only one shown) at one end of the beam 16 . A second chain loop 30 connects a smaller pulley 32 , which is mounted on the same axle as pulley 26 , to a free wheeling pulley 40 mounted at the other end of the beam. A bracket 42 , which is attached to the carriage 14 , also grips the second chain loop 30 .
[0021] As the carriage is forced back and forth along the beam, the second chain loop drives pulley 26 , and pulley 32 in turn drives pulley 22 . A one-way clutch on the axle of the fan (not shown in FIGS. 1 and 2 but seen in FIG. 3) permits pulley 22 to drive the fan in direction 21 when the carriage is moving in a driving direction 23 along the beam. When driven, the fan spins, generating air resistance in a manner described below. The air resistance is converted to a force that resists linear motion of the carriage and enables a user to exercise by pushing or pulling on the carriage.
[0022] The one-way clutch allows the fan to freewheel when the carriage is moving in a coasting direction 25 along the beam. The user may return the carriage to its original position in the coasting direction with little effort and then may repeat the cycle for repetitive exercise.
[0023] The relationship between the linear velocity of the carriage and the rotational velocity of the fan, and the corresponding relationship between the air resistance generated by the fan and the linear resistance on the carriage, are determined by the sizes of the pulleys. The sizes are chosen to provide an appropriate exercise experience.
[0024] The carriage is configured to enable the user to apply force by pushing or pulling through his arms and hands or by pushing his legs and feet, or by doing both. In other possible configurations, the user's legs and feet could be pulled to move the carriage.
[0025] A handle bar 60 is mounted on the carriage to permit pushing or pulling by hand. A pair of rigid straps 62 with hand stirrups 64 are attached to the handle bar to permit pulling by hand. The handle bar may be adjustably mounted so that the height may be set to suit the user and the type of exercise. Footrests 70 , 71 on either side of the carriage permit pushing with the feet.
[0026] A seat 72 (the seat is shown twice in FIG. 1, in two different positions, one position 72 a for pulling, the other position 72 b for pushing), includes a vertical seat back 80 and a horizontal seat bottom 82 .
[0027] In the pulling position 72 a, the seat bottom is on the other side of the seat back from the carriage. In that position, the user sits on the seat bottom facing the carriage and his chest is supported against the vertical face of the seat back as he pulls.
[0028] In the pushing position 72 b, the seat bottom is on the same side of the seat back from the carriage. In that position, the user sits on the seat bottom facing the carriage and his back is supported by the seat back as he pushes.
[0029] Other seat positions would also be possible such as one in which the user sits at the pull end and faces away from the carriage.
[0030] The seat back is mounted to the seat bottom through a bracket 89 that supports the seat back on one pivoting support 90 and a second adjustable support 92 that cooperates with a series of holes 94 on the seat back to permit the angle of the back to be adjusted.
[0031] The seat bottom 82 and the bracket 89 are part of a seat base 91 that also includes a square steel post 96 , which is held within one or the other of two square steel legs 100 , 102 located at opposite ends of the beam. The post 96 has a vertical column of holes 97 that cooperate with one or more holes in the sides of the beam legs to permit the height of the seat to be adjusted using pins.
[0032] The leg 100 on the pull end of the exercise machine has a foot 101 at its bottom end that rests on the floor. The leg 102 on the push end of the exercise machine has a foot 103 at its bottom end that also rests on the floor. The pull end leg 100 has a bracket 131 that is connected to and supports the bottom of the beam at the pull end. The push end leg 102 supports the push end of the beam indirectly on brackets 27 .
[0033] As seen in FIG. 3, the fan 12 includes a closed canister 123 (shown open in FIG. 3) comprising a cylindrical housing 122 and a lid 124 . As also seen in FIGS. 4 and 5, the fan includes a rotor 127 having a cylindrical cage 129 with a number (e.g., 32 ) of curved fan blades 131 arranged with equal spacing around the axis of the cage. The rotor has a flange 133 to permit the rotor to be mounted on a rotating disk. The rotating disk is attached to a hub which contains the clutch and bearings. The outer diameter of the rotor could be, for example, 14 inches, and the inner diameter of the cage housing 122 could be, for example, 18 inches, leaving a cylindrical open chamber ( 184 in FIG. 8) about 2 inches thick for circulation of air. When the rotor is being driven by motion of the carriage, it rotates in direction 141 shown in FIG. 5.
[0034] Referring again to FIG. 3, the lid supports a set of (e.g., eight) adjustable vanes 126 arranged in a circle at equal spacing around the axis of the lid to form a stator that interacts with the rotor through air flow within the canister to generate air drag. The stator also includes a bowl-shaped air deflector 130 mounted on the lid inside the ring of vanes.
[0035] As seen in FIG. 6, each vane 126 has an air deflection surface 140 in the shape of a section of a cylinder and a base 142 , which supports the air deflection surface. The base has a hole 144 that permits mounting the vane on the lid by a fitting that allows the vane to be rotated 146 around the fitting.
[0036] As seen in FIG. 7, on the outside of the lid, each vane has a positioning lever 158 that allows a user to turn the vane to a desired angular position to control the amount of air resistance generated by the fan.
[0037] The vane fitting resists rotation so that the user can adjust the vane by hand, and the vane will not shift from its adjusted position until adjusted again.
[0038] Referring again to FIG. 6, each vane can be adjusted from a fully closed position 148 to a fully open position 150 . In the fully closed position, the tip 151 of the vane almost touches the other end 152 of the next vane 153 of the ring. In the fully open position, the tip of the vane touches the inner wall of the canister housing when the canister is closed.
[0039] As shown in FIGS. 8 and 9, the housing 122 is deeper 180 than the height of the rotor. The remaining space accommodates the stator when the canister is closed. The stator is about the same height as the rotor.
[0040] The vanes of the stator can be adjusted between two extreme configurations. At one extreme, shown in FIG. 8, all stator vanes are turned to the closed positions. This effectively divides the outer end of the canister into two chambers, a round central chamber 60 surrounded by a cylindrical outer chamber 62 , with only a small amount of leakage ( 182 in FIG. 6) allowing air to flow between them. The outer chamber 62 is essentially an extension of the chamber that surrounds the rotor.
[0041] In the other extreme configuration, all vanes are open. The tips of all of the vanes touch the inner wall of the canister, effectively eliminating the outer cylindrical chamber 62 .
[0042] Although the exact details of the airflow within the canister are not known, it is believed that the following considerations apply.
[0043] Because of the one-direction clutch on the axle of the rotor, the rotor can only rotate in the direction 141 in FIG. 5, in which the curved vanes act as scoops to pick up air from the space within the rotor and direct it (arrows 191 ) to the cylindrical chamber outside of the rotor. This motion tends to set up a whirl of air 193 that rotates around the outer chambers of the canister in the same direction in which the rotor is rotating.
[0044] As seen in FIG. 8, when the stator vanes are in the fully closed configuration, the cylindrical chamber that surrounds the stator is in line with the donut shaped chamber that surrounds the rotor. Only a small proportion of the air leaks back 195 into the chamber within the rotor, where it is again thrown out into the donut-shaped chambers. Because there is relatively less re-circulation of the air within the canister the amount of drag resistance imparted to the user is also relatively less.
[0045] Conversely, when the stator vanes are in the fully open configuration, the air flow from the rotor is constantly striking the deflection surfaces of the stator vanes (shown, as to one stator 300 , in FIG. 9) and is being redirected 302 into the central part of the canister where it can be re-circulated by the fan. The redirection of the air is aided by the surface 134 of the air deflector 130 . As seen in FIG. 6, the vanes of the stator are oriented to have the opposite curvature of the vanes 131 of the moving rotor 127 .
[0046] Because there is relatively more re-circulation of the air than in the fully closed case, the amount of drag resistance is also relatively greater.
[0047] By adjusting one or more of the vanes, a range of configurations between the two extremes can be set, such as the one shown in FIG. 9. Because each vane can be adjusted to any position between open and closed, virtually any desired resistance level between those achieved by the two extreme configurations can be obtained.
[0048] In any of the stator configurations, the faster the fan is rotated, the more drag is created. A so-called drag factor accounts for changing conditions of the fan including airflow to the fan and air density. As explained, the configuration of the stator vanes alters the airflow to the fan. When all stator vanes are closed the drag for a given rotational speed will be lowest. Opening each stator vane will increase the drag by a factor of about 45%. With all stator vanes open, the drag factor is about 20 times greater than when all are closed. The large range of drag factor makes the exercise machine useful for a variety of strength training exercises.
[0049] Referring again to FIG. 1, a magnetic sensor 180 is attached to the fan canister to measure the speed of the fan. A cable 182 carries the information to a display 184 , which is mounted in a position where the user can see it easily. The monitor displays exercise performance values such as force, time, speed, work, power and repetition information. These values are based on the principles described in U.S. Pat. No. 4,875,674, incorporated by reference. Other embodiments are within the scope of the following claims. For example, other configurations of exercise positions, beams, and carriages can be used.
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An exercise machine in which a fan has a rotor that generates drag by causing air to move in response to exercising by a user. A deflection structure deflects air that the rotor has moved and is adjustable to control the amount of drag generated by the rotor.
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FIELD OF THE INVENTION
[0001] The present invention relates to safety improvements for airport taxiways and runways and particularly to the need to increase the width of taxiways and runways at airports in order to minimize the risk of foreign object damage to aircraft engines, as well as the safety issues regarding the deterioration of the existing natural grass surfaces bounding taxiways and runways.
BACKGROUND OF THE INVENTION
[0002] With the advent of larger and more powerful planes circulating on airport runways and taxiways that were constructed many years ago, there is a serious safety concern regarding overhanging engines which now frequently extend well beyond the existing runway and taxiway shoulders. The new generation of aircraft presently being manufactured have very large wing spans resulting in the jet engines overlapping the existing runway and taxiway shoulders, and in many cases actually hanging over the natural grass areas bounding the runway or taxiway, thus greatly increasing the risk of damage to aircraft engines by the presence of foreign objects.
[0003] The majority of airport runway and taxiway shoulders are constructed of asphalt which may have deteriorated surfaces and edges, such as cracking and spalling. This creates a serious risk of damage to aircraft and particularly aircraft engines overhanging the airstrip shoulders caused by foreign objects such as loose pieces of asphalt and debris that could be ingested by the aircraft engines. Foreign object damage is a primary safety concern for both airport operators and aircraft manufacturers since it could have catastrophic results. In addition to foreign object damage potential, asphalt pavements require periodic maintenance and/or complete replacement which adds to the overall airport operation costs.
[0004] In order to minimize the risk of foreign object damage to aircraft engines and in order to comply with regulatory safety issues, one solution is to increase the width of existing runways and taxiways using concrete or asphalt placed over deep bases in traditional construction methods. However, the costs related to traditional construction methods and to airport operation down-time resulting from the traditional construction are very significant and in some cases not feasible.
[0005] Air fields are generally constructed in large open areas and so in addition to jet blasts and vortex shedding, they are exposed to wind storms, ice and snow storms as well as sand storms, which requires expensive maintenance of existing topsoil bounding the runways and taxiways, such as cutting, grooming, cleaning, etc., in order to ensure efficient surface drainage of water, and to avoid water ponding and possibly freezing of the surface water on the runway.
[0006] Therefore, there is a need for improvement of airport runways and taxiways, particularly the need for improvements of the extension of existing runway and taxiway shoulders.
SUMMARY OF THE INVENTION
[0007] An object of the present invention is to provide a method for improving safety of airport runways and taxiways.
[0008] Another object of the present invention is to provide a cost-effective solution for the extension of existing runway and taxiway shoulders at airports in order to minimize the risk of foreign object damage to aircraft engines.
[0009] A further object of the present invention is to provide an airport runway and taxiway shoulder-bordering surface arrangement to extend the width of existing runway and taxiway shoulders, thereby reducing the potential for damage to aircraft engines by foreign objects.
[0010] In accordance with a general aspect of the present invention, there is provided a method for improving safety of airport airstrips comprising steps of:
[0000] a) providing a flexible surfacing material; and
b) extending the width of an existing shoulder of the airstrip by installing said flexible surfacing material along a side of said airstrip.
[0011] In accordance with a more specific aspect of the present invention, the method comprises the steps of: providing a compacted soil base bounding a shoulder of an airstrip; placing a flexible, water-impermeable surfacing material on the compacted soil base; and anchoring the surfacing material to the airstrip in a water-tight manner so that the surfacing material will assure efficient surface drainage of water and allow for unobstructed run-off of loose particles.
[0012] It is preferable to further lay a synthetic grass surface on an area beyond the surfacing material so that loose particles can be trapped thereby when being driven by jet blasts from the airstrip and running off the surfacing material.
[0013] In accordance with another aspect of the present invention, an airport runway and taxiway shoulder-bordering surface arrangement is provided to extend the width of existing runway and taxiway shoulders, thereby eliminating the potential for damage to aircraft engines by loose particles. The arrangement comprises a compacted soil base bounding an airstrip and a flexible water-impermeable surfacing material placed on the compacted soil base and directly adjacent to a side edge of the airstrip. Means are provided for anchoring the surfacing material to the edge of the airstrip in a water-tight manner so that the surfacing material will assure efficient surface drainage of water and allow for unobstructed run-off of loose particles. It is noted that the flexible water-proof surfacing material can be installed directly on the existing paved airstrip shoulder area in order to reduce the cost of excavating the existing asphalt and to keep the existing shoulder in place.
[0014] In accordance with a further general aspect of the present invention, there is provided an airfield safety arrangement for reducing the risk that an aircraft engine be damaged as a result of the ingestion of foreign objects from an area adjacent an airstrip, the safety arrangement comprising a ground surfacing material adapted to be laid down on the ground so as to extend laterally outwardly from an airstrip, the ground surfacing material having a relatively smooth shedding surface sloping downwardly from the airstrip to provide for surface water drainage and run-off of loose particles to a location wherein the particles are not subject of being ingested by the engines of the aircrafts on the airstrip, and an edge anchoring system for bonding the ground surfacing material in a water-tight manner to the airstrip. The surfacing material may be provided with a textured pattern as long as it does not impede run-off of loose particles.
[0015] Still in accordance with the present invention, there is provided an airstrip shoulder-bordering surface arrangement for extending the width of existing runway and taxiway shoulders in order to reduce the potential for damage to aircraft engines by foreign objects (FOD), the arrangement comprising a flexible water-impermeable surfacing material adapted to extend laterally of a side edge of an airstrip shoulder; and an edge-fastening system for securing the surfacing material in position relative to the airstrip shoulder and prevent water migration therebetween, the surfacing material having a relatively smooth top surface to provide for water surface drainage and unobstructed run-off of loose particles.
[0016] The surfacing material preferably further includes reflective and luminescent materials (for instance phosphorescent materials) to provide perimeter lines and runway identification markings so that in situations where the luminescent effect of the reflective materials has faded the aircraft lights would be reflected. The reflective or luminescent materials can be provided as an integral part of the surfacing material or can be applied thereon such as by bonding, painting or other by using any other appropriate techniques. The surfacing material is preferably in a green colour, or could be other colours if required to make a strong visual contrast between the runway and taxiway edges and the edge of the natural field.
[0017] In another embodiment of the present invention, the arrangement further includes a synthetic grass surface covering an area beyond the surfacing material which is permanently bonded to the surfacing material. Thus, the relatively smooth texture of the surfacing material will allow for unobstructed run-off of any loose particles that might be present on the runway and taxiway shoulders and could present a potential for foreign object damage to aircraft engines. As an added value, the replacement of natural grass surfaces with the surfacing material in combination with the synthetic grass surface can provide considerable cost benefits with regards to airport maintenance budgets. This artificial grass can be either permeable or impermeable depending on the specifications for the specific application.
[0018] Substantial savings in airport maintenance budgets can be achieved with the installation of the surfacing material which is virtually maintenance free. In addition, the installation of the synthetic grass surface would eliminate the need for the trimming and cutting of natural grasses. The artificial grass would retain its permanent green colour and texture throughout the year, thus eliminating the need to re-sod old and dead natural grass. In hot and arid climates, for example, in the Middle East, the relatively smooth shedding surface of the surfacing material would allow the removal of sand and other loose foreign objects quickly and efficiently from the shoulders simply as a result of the wind or air turbulence created by aircrafts or other mechanical means. Regular maintenance to keep the extended shoulders free of hazardous debris can be conducted easily, quickly and economically. The debris is displaced into the adjacent synthetic grass turf where the debris will be trapped. If necessary the accumulated debris can be vacuumed out periodically.
[0019] In cold climates accumulated snow can be easily and quickly removed from the surfacing material either by large blowers or sweepers, to a distance beyond the overhang of aircraft engines.
[0020] Since the surfacing material is completely water-tight, the risk of settlement and deterioration of the supporting base would be eliminated, thus providing a stable base for maintenance vehicle circulation year-round.
[0021] The pattern of installation of the surfacing material with the seams running parallel to the existing shoulder edges would not interfere with maintenance operations.
[0022] Other advantages and features of the present invention will be better understood with reference to preferred embodiments thereof described hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Having thus generally described the nature of the invention, reference will now be made to the accompanying drawings, showing by way of illustration a preferred embodiment thereof, and in which:
[0024] FIG. 1 is a perspective view of an airport runway having shoulder extensions in accordance with a preferred embodiment of the present invention;
[0025] FIG. 2 is a cross-sectional view of an airstrip shoulder-bordering arrangement in accordance with a first embodiment of the present invention; and
[0026] FIG. 3 is a cross-sectional view of an airstrip shoulder-bordering arrangement in accordance with a second embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0027] FIG. 1 illustrates an airport runway 10 comprising a central take-off/landing strip 11 and a pair of runway shoulders 12 . Each shoulder 12 is extended laterally outwardly by means of a shoulder-bordering arrangement comprising a soft ground cover or flexible water-proof surfacing material 14 .
[0028] As shown in FIG. 2 , the installation of the surfacing material 14 normally begins with a first step of removing the existing organic material contained in the uppermost stratum of the ground G bounding the shoulders 12 of the runway or taxiway which is generally referred to as an airstrip throughout this application, to a depth dictated by the soil report. The ground G is excavated down to a compactable earth surface. At that point, the soil is graded and compacted by being rolled and shaped to meet the required slopes such that the flow of surface water will be controlled to drain to specific locations. The rocks are removed from the compacted soil base and if required, a layer of engineered backfill will be installed and compacted prior to installing the surfacing material 14 directly on the compacted backfill if specified to do so. It is noted that in some applications, the surfacing material 14 may be laid down directly on the ground without the need for excavating.
[0029] The flexible surfacing material 14 , which is a plastic composite, for example polypropylene, urethane, vinyl or polyethylene, is laid directly on the compacted soil base adjacent to the edge of the existing airstrip shoulder 12 . As shown in FIG. 3 , the surfacing material 14 may also be installed so as to at least partly cover or overlap the shoulder 12 of the airstrip (i.e. the runway or the taxiway). This is particularly applicable in the case where the existing shoulder would have to be repaired or re-paved. The surfacing material 14 has a relatively smooth texture having a thickness of between 50 mm and 400 mm. The surfacing material 14 can be provided in the form of a polyethylene, polypropylene or any other type of plastic or composite material that can be sprayed or laminated upon a mesh substrate. The polyethylene or any equivalent thereof could be sprayed or applied by various methods on site or at the manufacturing plant. The surfacing material 14 is completely water-impermeable and is preferably permanently bonded to an edge-fastening system or anchoring system 16 placed next to the existing airstrip shoulder edges or to the shoulder 12 directly since all installations are different.
[0030] The installation of the surfacing material 14 is completed by overlapping rolls of the surfacing material and applying a heat treatment, such as thermal welding, or by applying adhesives to the overlapping surfacing materials, thus fusing the two materials together to obtain a permanent, water-tight and strong bonding of the seams.
[0031] In the illustrated embodiment, the surfacing material 14 is bonded in a water-tight manner to the airstrip shoulder 12 . More particularly, the interface between the edge of the existing airstrip shoulders and the first roll of the surfacing material can be made water-tight by installing impermeable elastomeric sealers in order to assure a continuous and uninterrupted surface drainage of the impermeable surface. The impermeable elastomeric sealer is incorporated with the specially designed anchoring system 16 which assures the safe, permanent and economical anchoring of the edges of the surfacing material 14 to the immediately adjacent existing airstrip shoulders 12 .
[0032] The anchoring system 16 preferably includes a prefabricated, extruded plastic member 18 , for example polypropylene or other plastic that can be thermally bonded to the flexible surfacing material 14 . The extruded plastic member 18 is partially embedded in specially formulated expanding foam 20 which is injected into a narrow excavated trench along the edge of the airstrip shoulder 12 . The excavation, injection of foam, and bonding of the plastic member 18 are completed simultaneously in one operation. The plastic member 18 has an anchoring portion 24 from which extends a leg 26 supporting an above-ground section or head 22 to which the first row of surfacing material 14 is thermally or mechanically bonded. For instance, bonding of the surfacing material 14 can be done by applying a heat activated treatment or by applying adhesives to the overlapping of the surfacing material 14 and the extruded plastic member 18 , thus permanently fusing the two materials together. This anchoring system 16 provides a water-tight seal between the airstrip shoulder edge and the surfacing material 14 . A sealer 27 is preferably provided along the vertical interface between the shoulder 12 and the ground surfacing arrangement, as shown in FIG. 2 .
[0033] When the entire surfacing material 14 is in place, the surfacing material 14 will take the shape and the slope of the underlying compacted soil base and will stay flat to provide the relatively smooth shedding surface to provide for water drainage and run off of loose particles. The extent in width and length to which the surfacing material 14 is installed will depend on the performance and design criteria of the specific sites. The areas beyond the surfacing material 14 could be covered with artificial grass 30 which would trap any born particles, such as sand displace by aircraft. The synthetic grass surface is permanently bonded to the surfacing material 14 such as by applying the thermal welding technique or by applying adhesives to assure a permanent water-tight seam between the surfacing material 14 and the synthetic grass surface 30 .
[0034] The synthetic grass surface 30 generally includes a pile fabric 32 which is preferably placed over a compacted soil base substantially free of organic matter. The pile fabric 32 includes a plurality of pile elements 34 resembling blades of grass and extending from a relatively thin and flexible backing mat 36 to a predetermined height thereabove. A non-water retaining ballast material 38 for stabilizing the pile fabric 32 in place is provided on the backing mat 36 and has a thickness less than the predetermined height of the pile elements 34 . The ballast material 38 is provided in the form of a relatively thick layer of particulate material dispersed among the pile elements 34 on the backing mat 36 . The synthetic grass is typically installed on a sloped base for directing water from the pile fabric 32 to the designed storm water management system. Surface drainage is important since it is easier to prepare and can work at lower cost.
[0035] The rows of pile elements 34 can be similar to that described in Applicant's co-pending Canadian Patent 2,218,314 filed on Oct. 16, 1997, and laid open on Sep. 10, 1998, the contents of which are incorporated herein by reference.
[0036] A thin impermeable membrane 40 is laid on the compacted soil base to prevent water from percolating down thereto. A drainage enabling layer 42 which comprises a thick layer of aggregate, such as rock particulates, is provided on the impermeable membrane 40 . The flexible baking mat 36 is placed on the drainage enabling layer 42 so that the water can readily flow from the backing mat 36 through the drainage enabling layer 42 onto the impermeable membrane 40 and into storm sewers placed at strategic locations. This embodiment is described with more details in Applicant's PCT application PCT/CA01/01275, entitled ARTIFICIAL GRASS FOR LANDSCAPING, filed Sep. 5, 2001, the specifications of which is incorporated herein by reference. It is noted that the water barrier could be integrated to the backing mat 36 in which case the infill layer 38 would act as the drainage enabling layer.
[0037] As shown in FIG. 2 , the surfacing material 14 can be bonded to the edge of the impermeable membrane 40 to provide a water-tight seal between the synthetic grass surface 30 and the surfacing material 14 . Alternatively, the surfacing material could be placed underneath the backing mat 36 and be thermally or adhesively bonded thereto.
[0038] As an added safety feature, the surfacing material 14 can be fabricated with a permanent colour such as green, or with other colours if required to enhance visual contrast between the central landing zone of the airstrip 10 and the shoulders 12 thereof. The surfacing material 14 can also be designed to accept solar energy absorbing fabrics which will dissipate a luminescent glow during the night without the need of outside power sources. The luminescent reflective glow would last up to 10-12 hours to cover the dusk to dawn period. The solar absorbing fabric can be coated directly onto the installed surfacing material 14 or can be installed during fabrication. Patterns spacing and shape factors can be custom fabricated to meet specific airport operation specifications. The solar absorbing fabric can advantageously replace conventional lighting systems for small airports.
[0039] The surfacing material 14 can further include special reflective fabrics installed thereon to enhance the visibility of the runway path for aircraft landing during the night. Thus in situations where the luminescent effect of the solar absorbing fabric fades, the aircraft lights will be reflected by the one-way reflective fabrics to facilitate safe landing.
[0040] As shown in FIG. 3 , the surfacing material 14 can be installed directly on an existing shoulder 12 and anchored thereto by means of an anchor member 18 ′ provided in the form of a plastic extrusion placed in a trench formed in the shoulder 12 and fixed in position therein by means of a plurality of anchoring bars. The surfacing material 14 can be thermally or adhesively bonded to the anchor member 18 ′ or even mechanically attached thereto, as described hereinbefore with respect to FIG. 2 . Alternatively, the surfacing material 14 could be adhesively bonded directly to the shoulder 12 . A given thickness of material is removed from the shoulders 12 so that the surfacing material 14 is substantially flush with the take-off/landing strip 11 .
[0041] Protection against foreign object damage (FOD) can be further enhanced by incorporating a guidance system into the surfacing material for guiding a robot 48 parallel the runway 10 in order to locate and detect FOD materials that could be ingested by the aircraft engines. The guidance system could include a magnetic guidance wire 46 embedded in the surfacing material 14 or any other type of guidance technology.
[0042] By having guidance wires embedded into the flexible surfacing material 14 , drainage of the runway would not be impeded by channels or protruding edges to guide the robots 48 . The robots 48 could also be designed to clear the flexible fabric of sand and FOD by means of having a larger robot made with the necessary blowers to do so. The FOD detecting robot would need to be heavy and stable enough to not be displaced from the wind and or jet wash. A cable system could also be used to guide the robot along and keep the robot tethered.
[0043] Modifications and improvements to the above-described embodiment of the present invention may become apparent to those skilled in the art. The foregoing description is intended to be exemplary rather than limiting. The scope of the invention is therefore intended to be limited solely by the scope of the appended claims.
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Safety improvements of airport runways and taxiways are achieved by providing a flexible, water-impermeable surfacing material on a compacted soil base directly adjacent to an edge of airstrip shoulders. A synthetic grass surface is provided on the area beyond the surfacing material so that foreign objects such as loose particles of the airstrip shoulder materials will be driven by jet blasts and run-off across the relatively smooth texture of the surfacing material and will be trapped by the synthetic grass, thereby minimizing foreign object damage to aircraft engines, particularly to those overhanging engines which extend well beyond the existing runway and taxiway shoulders.
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CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This United States Application claims priority to British Patent Application No. 0710034.0 filed 25 May 2007.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable
THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT
[0003] Not Applicable
INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC
[0004] Not Applicable
BACKGROUND OF THE INVENTION
[0005] The invention to which this application relates is a power tool in the form of a planer which can be used to remove portions of material from a workpiece surface along which the planer is moved.
[0006] The planer includes a base surface which is used to contact the surface of the workpiece from which the material is to be removed. A drum is provided within the housing which is positioned adjacent to the base and the drum includes one or more blades mounted thereon. The drum protrudes a selectable distance from the base and the blades, as they rotate, cause removal of the material of the workpiece. The drum is typically driven by connection to a motor located in the housing. The motor is preferably mounted substantially above the drum with respect to the workpiece on which the planer is being used. In addition, debris removal means can be provided within the housing in the form of one or more channels which depend from the chamber in which the blade drum is mounted to one or more openings in the housing and which allow debris to be moved from the blade chamber and deposited to the rear or side of the planer.
[0007] This form of planer is relatively well known, and there are numerous patents in relation to the same. One known problem with planers is that access to certain surfaces which are to be planed can be difficult due to protrusions on the side walls of the planer clashing with parts of the workpiece. This, in combination with the fact that the edges of the blades of the drum are offset from the edge of the planer housing, means that there can be portions, particularly side edges, of the workpiece which are not accessible by the planer to plane the same. A further problem is ensuring that the safety requirements for use of the planer can be achieved whilst trying to ensure the widest possible application of the planer.
[0008] An aim of this invention is to provide further improvements to the planer which render the use of the same more effective and efficient for the user.
BRIEF SUMMARY OF THE INVENTION
[0009] In a first aspect of the invention, there is provided a planer power tool. The tool incorporating a base which contacts with a workpiece from which portions of material are to be removed by the tool passing therealong, and a housing depending from the base and in which is mounted a drum in a chamber. The drum includes at least one blade mounted thereon. The drum is driven by a motor provided as part of the tool to rotate and move the blades into contact with the workpiece to remove material therefrom. There is provided a guard located to be movable between first and second positions, a first position masking an opening to one side of the chamber in which the blade drum is mounted, and a second position in which the opening to the chamber is exposed.
[0010] Typically, the guard has two movement components between the first and second positions, one movement component being a pivotal movement between the first position and an intermediate position. Typically, a pivot axis, about which the guard moves, is located at an offset distance from the opening into the chamber. In one embodiment, the pivot axis is located towards the front of the planer from the chamber.
[0011] Typically, the guard is movable between the first and second positions via user manipulation of an actuation means, such as a lever or slide (hereinafter referred to as a lever). The lever is located on the housing at a position remote from the guard. Typically, the lever is located at a position at which the same can be operated by the user when gripping the planer in normal operation.
[0012] Typically, the lever is mounted adjacent to a gripping handle provided on the housing. In a preferred embodiment, movement between the first, closed and second, opened positions comprises the guard moving pivotally in the first movement component from the closed position to an intermediate position removed from the chamber opening and then from the intermediate position to the second, opened position in which the guard moves into a recess so that the external surface of the guard lies substantially flush with the adjacent side wall of the housing.
[0013] Typically, movement from the second, opened to the first, closed position involves an axial movement to the intermediate position and then a pivotal movement to the first, closed position.
[0014] The provision of the two movement components allows the guard, when in the opened position, to have its external surface lie substantially flush with an adjacent external surface of the housing. The axial movement between the opened position and the intermediate position allows the guard to be moved clear of an external surface of the housing and then allows the same to be pivotally movable to the closed position.
[0015] When in the opened position, as the guard lies flush with the housing side wall, the guard does not provide any obstruction on the side wall to the use of the planer, and as a result the planer can be used to cut relatively confined rebated surfaces without limitation. Thus, as and when required, the user can select to move the guard to the second, opened position in the recess to be able to bring the edge of the blade of the drum closer to the edge of a workpiece than would be possible if the guard was in the first, closed position.
[0016] Furthermore, preferably, the guard is required to be held in the opened position by the user holding the same open by holding the lever. This means that both of the user's hands are holding handles on the planer in use and, therefore, are well removed from the opened drum chamber and, therefore, provide the required level of safety.
[0017] In one embodiment, the lever is movable around an arcuate guide which, in turn, operates a rack connected to a pinion which, in turn, is located with the guard.
[0018] In one embodiment, the rack includes one or more ramps which force the guard to move between the intermediate position and the opened position as the lever is moved, such that the guard movement occurs automatically with a single movement of the lever by the user.
[0019] In a further aspect of the invention, there is provided a power tool planer incorporating a base which contacts with a workpiece from which portions of material are to be removed by the tool passing therealong and a housing depending from the base and in which is mounted a drum in a chamber. The drum includes at least one blade mounted thereon. The drum is driven by a motor provided as part of the tool to rotate and move the blades into contact with the workpiece to remove material therefrom, wherein there is provided a guard selectively positionable in a recess in the housing such that the external surface of the guard lies substantially flush with an adjacent side wall of the housing.
[0020] In a further aspect of the invention, there is provided a power tool planer incorporating a base for movement along a workpiece to remove material therefrom, a housing, and a drum mounted within a chamber in the housing. The drum incorporates one or more blades. The tool being provided to be moved in a forward direction to allow removal of material from the workpiece as the blade drum is driven by a motor provided as part of the tool. The power tool further includes a dust and debris extraction system incorporating at least one passage depending from the chamber along which dust and debris created during the use of the power tool can pass. The passage leads to a diversion device selectively connectable with first and second exit ports, a first port mounted on one side of the housing and a second port located on the opposing side of the housing or rear of the housing. The diversion device incorporates a rotatable assembly which can be selectively positioned to cause the dust and debris from the passage to exit via the first or second port.
[0021] Typically, the diversion means incorporates a user actuable member positioned externally of the housing which can be moved by the user to select from which of the two ports the dust or debris leaves the housing. Typically, the actuation member is formed to provide a visual indication of which of the ports dust or debris will leave the housing. Typically, the visual indication is provided in the form of a pointer and a label to point toward the particular port which is opened at any given time.
[0022] Typically, the diversion means includes a diverting assembly to seal off the port not used for extraction of the dust. Typically, the diverting assembly is formed with a channel, such that dust and debris is efficiently obtained from the passage which extends substantially across the width of the drum.
[0023] Typically, the diverting assembly is provided such that the passage of the dust and debris through the diverting assembly is along a channel of substantially the same width as the passage leading from the chamber. This, therefore, means that the opportunity for dust or debris to clog up the diversion means is minimized. In one embodiment, the channel is shaped such that the passage of the dust and debris is accelerated through the passage.
[0024] In a further aspect of the invention, there is provided a power tool planer incorporating a base to contact the surface of a workpiece from which material is to be removed by use of the power tool, a housing depending from the base and, within the housing, there is provided a drum with one or a plurality of blades mounted thereon, which drum is selectively positionable with respect to the base of the tool to determine the depth of cut by the blade, and wherein there is provided an assembly to allow the depth of cut to be adjusted by a user. The assembly includes an axial member connected to the base to cause movement of the base with respect to the drum to adjust the depth of cut, and a gear assembly connected to a winder. The winder selectively actuable by the user to move the axial member.
[0025] In one embodiment, the axial member incorporates a carrier on which a plurality of planetary gears are mounted in conjunction with a sun gear. The planetary gears and sun gear are mounted within an outer ring also located on the carrier and the winder is located to cause rotation of the gear assembly and, hence, movement of the carrier with respect to the housing on which the same is mounted. Typically, the carrier axial member is mounted within an enclosure provided in a fixed relationship with the housing.
[0026] The dust and debris extraction means and/or depth adjustment means and/or movable guard are preferably all provided on the same planer but can be provided independently of each other.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Specific embodiments of the invention will now be described with reference to the accompanying drawings, wherein:
[0028] FIG. 1 illustrates a perspective view of the planer tool in accordance with one embodiment of the invention;
[0029] FIG. 2 illustrates the forward portion of the tool of FIG. 1 in detail showing the drum guard in a closed position;
[0030] FIG. 3 illustrates the portion of the tool of FIG. 2 with the drum guard in an opened position;
[0031] FIG. 4 illustrates a top portion of the tool of FIG. 1 with a user actuation lever for the drum guard;
[0032] FIG. 5 illustrates a top portion of the tool of FIG. 1 with an alternative arrangement of the user actuation means for the drum guard;
[0033] FIGS. 6 and 7 illustrate internal views of the housing of the tool showing a mechanism for movement of the drum guard in accordance with one embodiment;
[0034] FIG. 8 illustrates a rear portion of the tool of FIG. 1 showing a dust extraction port;
[0035] FIG. 9 illustrates a dust and debris diverting assembly in accordance with one embodiment of the invention;
[0036] FIGS. 10 a and b illustrate a dust and debris extraction system and casing therefore;
[0037] FIG. 11 illustrates the further embodiment of the invention showing a depth adjustment means; and
[0038] FIG. 12 illustrates an exploded diagram of the depth adjustment means of FIG. 11 .
DETAILED DESCRIPTION OF THE INVENTION
[0039] Referring first to FIG. 1 , there is illustrated a planer power tool 2 . The power tool incorporates a base 4 designed to pass along a workpiece surface (not shown) from which portions of material are removed using the tool. The tool has a front end 6 and is designed to be moved in a direction of arrow 8 along a workpiece. The power tool has a housing 10 in which is located a motor 12 connected to drive and rotate a drum 14 mounted in a chamber 16 . The drum has a plurality of blades 18 at spaced intervals there around and is designed to be rotated about an axis 20 by the motor. The base position with respect to the drum can be selectively adjusted via adjustment means 22 by a user to control the depth from which the blades protrude below base 4 and, hence, select a depth of cut made on a workpiece. Dust and debris extraction means can be provided, and these will be described subsequently in more detail. A user grips the power tool via handles 24 and 26 to guide movement of the tool along a workpiece.
[0040] FIGS. 2 and 3 illustrate a first aspect of the invention in more detail, and this relates to the provision of a guard 30 mounted movable between a closed position, shown in FIG. 2 , and an opened position, shown in FIG. 3 . The guard is provided to allow selective access to opening 32 of chamber 16 in which drum 14 is located. This may normally be required to allow the removal of the drum for cleaning and/or removal of debris from the chamber and/or to allow one or more blades mounted on the drum to be removed.
[0041] The guard is movable between opened and closed positions about a pivot axis location 34 and, in accordance with the invention, is movable with two movement components. Thus, from the second, opened position, shown in FIG. 3 , to the first, closed position of FIG. 2 , the guard is first moved with an axial component from the recessed open position, outwardly of the housing as indicated by arrow 36 . Once the guard is then clear of a side face 38 of the housing and has hence moved from a substantially flush recessed position, the guard can then pivotally move about pivot axis location 34 , as indicated by arrow 39 , to the first, closed position in FIG. 2 . To move from the closed position of FIG. 2 to the opened position of FIG. 3 , the first movement is pivotal as indicated by arrow 41 in FIG. 2 and then inwardly, as shown by arrow 43 , to move the guard to the recessed position of FIG. 3 .
[0042] This movement can be achieved via user manipulation of an actuating device 40 which, in the case of FIG. 4 , is a lever and in the case of FIG. 5 is a slide. In each case, actuating means 40 is located adjacent to handle 24 to allow the same to be operable by a user while holding the planer tool in use via handle 24 . In both cases, the movement of the actuating means, whether that be in a straight line or an arcuate line, causes operation of a mechanism connected to the guard, an example of which is shown in FIGS. 6 and 7 . The example is shown with the housing removed for ease of reference. Actuating means 40 shown in this case is of the type shown in FIG. 4 , but it should be appreciated that operation is similar regardless of the actuating device 40 used. Preferably, the guard is biased to the closed position via one or more resilient means, such as springs
[0043] The resilient means is located to provide biased movement with respect to the two components of movement. This, therefore, means that as soon as the actuating means is released when the guard is in the opened position, the guard will automatically return to the closed position.
[0044] In one embodiment, a compression spring is provided for the axial movement component and a torsion spring is provided for the pivotal movement component. In one embodiment, the biased movement is damped to prevent damage to the guard and/or workpiece.
[0045] Typically, the actuating means will include a pointer or other indication means to indicate the position that the guard is in at any given instant.
[0046] In one embodiment, the guard, in addition to being movable under the influence of the actuating means, is also movable if it impacts with a workpiece surface such that as the planer is moved forward the guard may be moved to the opened position by impact with a workpiece, thereby allowing continued operation of the planer along the intended line of operation.
[0047] When the guard is in the opened position, the drum can be removed by insertion of a tool into the drum shaft to release a fastener and allow removal of the drum
[0048] In FIGS. 6 and 7 , the actuating means 40 is movable along an arcuate guide 44 and is connected to move a rack 46 . The rack is connected to a pinion 48 which, in turn, is connected to guard 30 to cause pivotal movement of the same as the rack moves and the pinion rotates. Also, provided on the rack are ramp portions 50 which cause the guard, when it reaches the intermediate position, to then move axially with respect to the axis and, hence, move to the flush, opened position or alternatively move in the reverse direction away from the flush position to the intermediate position which is clear from the housing.
[0049] The ability to move the guard to the opened recessed position means that the planer housing can be moved closer to an edge or obstruction when the same is being moved along a workpiece and, therefore, increases the accessibility of the planer in terms of possible locations of use.
[0050] Also, provided within the housing in a further aspect is a dust and debris collection device. This collection means incorporates a passage 60 which passes from a rear of chamber 16 in which the blade drum is located, and which passage leads to a diversion means 62 located to the rear of the chamber. The diversion means is connected to an external member 64 which is preferably formed with a pointer 65 for reasons which will be described subsequently. The member is connected axially to a diverting assembly 66 , illustrated in FIG. 9 , and is located with respect to first and second ports 68 on one side of the housing and 70 on the opposing side of the housing via casing 81 of the diversion means shown in FIG. 10 b and in which the diverting assembly 66 is mounted and which is located in the housing of the tool as shown in FIG. 10 a . At any given time, one of the ports 68 , 70 can be opened and the other port can be closed via the diverting assembly, depending on the position of the diverting assembly with respect to the ports.
[0051] The diverting assembly incorporates a channel 71 which is preferably of substantially the same width as passage 60 which leads from the chamber, thus ensuring that the volume of debris from passage 60 can pass through channel 70 of the diverting assembly without the same causing clogging up or blockage of the overall dust extraction system. The diverting assembly also has a wall 72 positioned adjacent one of the ports to cause that port to be sealed and closed. The movement of the diverting assembly is achieved via actuating means 64 mounted on a spigot 76 of the assembly, and the diverting assembly is, in turn, mounted within a casing 81 which serves to locate and guide movement of the diverting assembly. Typically, actuating member 64 is located and formed with pointer 65 to indicate to a user which of the ports is open at any given time, typically in conjunction with a label or other indication means (not shown) applied to the housing.
[0052] Furthermore, an inside wall 82 of the diverting assembly is designed to accelerate the dust or debris from passage 60 (which is indicated by the arrows 78 in FIG. 9 ) via the shape of wall 82 towards the particular port (as indicated by arrows 83 ) which is opened at that time and into, typically, a vacuum adaptor or dust collection bag connected to the port. The acceleration of dust or debris from the housing clears the area around the drum and, thus, prevents the opportunity of clogging and also forces the dust or debris into the bag collection means.
[0053] FIGS. 11 and 12 illustrate a further embodiment of the invention in which there is provided a depth of cut adjustment mechanism 84 . In this case, the depth of cut can be created by the user rotating a winder 86 which is connected to a gear assembly 88 which comprises three planetary gears 90 , on spigots 93 and a sun gear 92 which are located within an outer ring 94 . The provision of the gear assembly, which is located on axial carrier 96 , is to allow adjustment of the base of the planer with respect to the drum and, thereby, allow the depth of cut to be adjusted by a free end 98 of the carrier contacting the base. This means that the rotation of winder 86 by a user is amplified by the gear assembly and, hence, amplifies the input force and increases the number of rotations required to index a front shoe. This, therefore, means that less input force is required from the user, and improved control and greater resolution of a particular depth, which is set via the control device, is achieved. In addition, a particularly effective scale can be provided by providing a pointer 85 on the fixed outer ring 94 and a scale (not shown) on the moving portion of carrier 96 so that the user can easily see the particular adjustment which is being made. The rotation may also be provided in a detented manner.
[0054] The improvements as herein defined, independently or in combination, provide effective benefits to the use of the planer and as a result the user thereof.
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The invention provides a power tool planer which includes a drum with at least one blade thereon located within a chamber in the tool housing. One end of the chamber is provided with an opening which can be selectively closed by a guard. The guard can be moveable between a first closed position and a second position in which the chamber is opened, and the guard is moved into a recess in the housing to improve the ability to use the tool in confined spaces, as the guard lies flush with a side wall of the housing. Also provided is a dust and debris extraction system and a means for adjusting the depth of cut obtained using the tool.
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BACKGROUND OF THE INVENTION
This patent application claims the benefit of U.S. Provisional Patent Application No. 60/704,785 filed Aug. 2, 2005; U.S. Provisional Patent Application No. 60/704,786 filed Aug. 2, 2005; U.S. provisional Patent Application No. 60/704,787 filed Aug. 2, 2005; each sequentially entitled as: “Vehicle Parking Security System-Unique Characteristics Database Stored”; “Vehicle Parking Security System-Vehicle Characteristics Tied to Parking Ticket/Tag”; and “Vehicle Parking Security System-Vehicle Signature Tied to Parking Ticket/Tag”. The Graphs or Tables, the method of use, the advantages and additional characteristics and the functionality of the three (3) U.S. Provisional Patent Applications are included herein and as referenced thereto. The original concept of “vehicle” is expanded herein to include applications for any “mobile entity” when suitably adapted to said applications.
Throughout this disclosure, the following applies:
a) secure, securing, secured or securable also connotes control, controlling, controlled or controllable and/or protect, protecting, protected or protectable where/as applicable and/or appropriate;
b) vehicle connotes any mobile entity including one moved by another vehicle such as a cargo container, skid, trailer, et. al.;
c) mobile entity connotes any/all transportables whether self-powered vehicles such as autos or trucks or transported by auxiliary means/methods such at transporting trailers, cargo containers, cartons, skids/pallets, et. al.; and
FIELD OF THE INVENTION
This invention is a method, apparatus and system for detecting the presence of a specific mobile entity and securing same in a defined area or under definable control parameters.
In one form the invention relates to a method, apparatus and/or system for detecting the presence of specific/discrete mobile entities and securing areas (or routes) of use, presence, storage and/or transport of said mobile entities (vehicles) for simplicity of conceptual invention understanding only. The invention in another form relates to a new and useful system and method for recognizing a vehicle which has been pre-identified through the use/means of an “Onboard Identity” (OI) as a “signature” (SI) vehicle (entity), i.e., having a pre-defined/detectable onboard identity, before access to a secured area. Additionally and/or alternately the invention may be directed to or include identifying key characteristics of an entering non-OI equipped vehicle and creating a vehicle Characteristics Identity (CI) based upon physical and/or discrete, information (e.g., license plate, VIN (vehicle identification number, identification tag/seal, color, shape, manufacturer, year and model details, physical/structural features, et. al.) of the entering vehicle, all captured prior to entry to a secured or securable area. Additionally, the invention relates to further features of the system, which may or may not apply in all cases, to provide for identification of the vehicle which entered as authorized to exit, pass through or depart primarily based upon confirmation of the identical nature of the exiting vehicle via the onboard OI or the CI created for that vehicle upon its entry and the proper/authorized use by the party responsible for the exiting vehicle of the Ticket/Tag which was issued upon entry.
DESCRIPTION OF THE PRIOR ART
Applicant and inventor hereof is not familiar with any presently operating systems which carry out the functions and provide for the many features and advantages of the present invention in any manner and particular in no manner as disclosed herein by the Applicant.
Applicant strongly contends that there is substantial and significant value in being able to effectively identify, monitor and in some circumstance even control vehicle access to and exit from a secured area such as a parking lot, staging/storage area or a public, private or government facility of any type or configuration where security can be reasonably exercised. It is important to note that the so called “secured area” could and does include “definable areas/zones” of any type accessed by mobile entities (vehicles) including but not limited to towns, cities, tunnels, bridges, terminals of any type (bus stations, train stations, airports, subways, depots and the like).
There is nothing currently available which satisfies these needs and objectives. However, the invention disclosed herein does meet all of these objectives.
SUMMARY OF THE INVENTION
This invention most generally relates to a system for protecting, controlling and securing a region entered and exited by vehicles. The system in one aspect comprises a means for obtaining a vehicle identification information relative to an entering vehicle, wherein the vehicle identification information is either an onboard-identity/signature or a non-onboard-identity/signature sometimes identified as a vehicle characteristic. The non-onboard-identity/signature vehicle as a characteristic identity, is derived from at least one readable feature of the entering vehicle. These readable features could be one or any combination of features such as manufacturer, model, year, VIN, physical size, color, shape and registration/license tag.
Thus, one aspect of the invention is to provide a system and method for identifying, relating, rejecting or accepting an entering vehicle as a vehicle with no potential problem as the vehicle enters into a protected or protectable area or region.
Another aspect of the system and method is to provide the entering vehicle operator with a form of document or a ticket/tag which is randomly coded to the entering vehicle identification.
A further aspect of the invention is to provide for additional data associated with the entering vehicle such additional data may be the date and time of entry.
An additional aspect of the invention is to provide means and method for obtaining vehicle identification information for an exiting vehicle and comparing such exiting vehicle identification with the vehicle identification of entering vehicles for a matching review of stored data thereby allowing exit of the vehicle based upon the finding of a matching identification, or not allowing the exit of the vehicle if no matching is found in the stored data base.
A still further aspect of the invention is to provide a means and method for comparison and review of the obtained identification information of the entering vehicle with stored information. The stored information being information entered by or from other locations for identification and/or tracking purposes of any type such as securing/quarantining/isolating potentially problem vehicles of any type.
It is clear that there may be variations in the information sensing devices, the computer or system components related to capturing, storing, searching and/or retrieving data/information from files or storage means of any type and making comparisons and matching or confirmations of a vehicle with stored data. However, the main features are consistent and are;
1) Having a method and means for identifying a vehicle at a specific location of the secured area referred to as the entry location or position by:
a) sensing an Onboard Identity (OI) code of the vehicle if the vehicle has such a code when it arrives; or
b) creating a suitable Characteristics Identity (CI) for a non-Onboard vehicle by detection of select characteristics of the vehicle such as manufacturer, year, registration, license plate, VIN, identification tag/seal, color, shape, model details, physical/structural features, et. al.;
2) Creating the vehicle Signature (SI) assigned to the vehicle for use while in the confines of the defined area/zone being accessed, i.e., there is a creation of a vehicle-specific/unique signature such as but not limited to a random and encoded sequence of numbers, characters and/or letters as the vehicle SI;
3) The vehicle OI and/or (select) sensed characteristics composing the CI can be provided to data storage systems for future use if/when needed for comparison and review of matching information with stored information or information entered by or from other locations for identification and/or tracking purposes of any type such as securing/quarantining/isolating potentially problem vehicles of any type;
4) A vehicle within a secured area may exit the secured area:
a) after #1 above is repeated to re-establish/verify the OI signature and/or CI of the departing vehicle's signature to confirm departure is authorized;
b) a database/system verification of the vehicle's overall SI produces no results and/or information indicating the vehicle must/should be detained for any reason; and
c) if any applicable, proper payment is made based upon the time and date of entry and exit of the vehicle when the system is used for security and/or control and/or protection of a parking or storage area.
These and further objects of the present invention will become apparent to those skilled in the art to which this invention pertains and after a study of the present disclosure of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Included herewith in this application are three (3) drawing figures each of which is a flow diagram of the various functional components of the system of this invention and showing the relationships and association of entering and/or exiting mobile entities, the information obtained and evaluated and the path of action taken upon evaluation of the data collected and/or stored. The character of the operation of the invention is represented and the secured or securable area, also identified as a controlled and/or protected area, would include those elements of the system determined to be essential for the particular characteristics of the area to be secured (controlled and/or protected).
FIG. 1 . is a flow chart representation of one embodiment of the invention which includes elements for managing entering and exiting mobile entities;
FIG. 2 . is a flow chart representation of another embodiment of the invention which includes only elements directed to managing entering mobile entities; and
FIG. 3 . is a flow chart representation of still another embodiment of the invention which includes elements directed to managing exiting mobile entities.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Throughout this disclosure, the following identification of elements and features of the invention applies:
a) secure, securing, secured or securable also connotes control, controlling, controlled or controllable and/or protect, protecting, protected or protectable where/as applicable and/or appropriate;
b) vehicle connotes any mobile entity including one moved by another vehicle such as a cargo container, skid, trailer, et. al.;
c) mobile entity connotes any/all transportables whether self-powered vehicles such as autos or trucks or transported by auxiliary means/methods such at transporting trailers, cargo containers, cartons, skids/pallets, et. al.;
d) In any and all applications relating to the collection and use of data, details, and the like, one's right to privacy must not to be violated unless so approved and properly documented by the responsible authorities.
The following is a description of the “preferred” embodiment of the invention providing for mobile entity (vehicle) security in an area/zone which is accessed, passed through, or provides mobile entity storage for any reason. It is clear that there may be variations in the information sensing devices, the computer or system components related to capturing, storing, searching and/or retrieving data/information from files or storage means of any type and making comparisons and matching or confirmations of a vehicle with stored data. However, the main features are consistent and are;
1) Having a method and means for identifying a vehicle at a specific location of the secured area referred to as the entry location or position by:
a) sensing an Onboard Identity (OI) code of the vehicle if the vehicle has such a code when it arrives; or
b) creating a suitable Characteristics Identity (CI) for a non-Onboard vehicle by detection of select characteristics of the vehicle such as manufacturer, year, registration, license plate, VIN, identification tag/seal, color, shape, model details, physical/structural features, et. al.;
2) Creating the vehicle Signature (SI) assigned to the vehicle for use while in the confines of the defined area/zone being accessed, i.e., there is a creation of a vehicle-specific/unique signature such as but not limited to a random and encoded sequence of numbers, characters and/or letters as the vehicle SI;
3) The vehicle OI and/or (select) sensed characteristics composing the CI can be provided to data storage systems for future use if/when needed for comparison and review of matching information with stored information or information entered by or from other locations for identification and/or tracking purposes of any type such as securing/quarantining/isolating potentially problem vehicles of any type;
4) A vehicle within a secured area may exit the secured area:
a) after #1 above is repeated to re-establish/verify the OI signature and/or CI of the departing vehicle's signature to confirm departure is authorized;
b) a database/system verification of the vehicle's overall SI produces no results and/or information indicating the vehicle must/should be detained for any reason; and
c) if any applicable, proper payment is made based upon the time and date of entry and exit of the vehicle when the system is used for security and/or control and/or protection of a parking or storage area.
The fundamental characteristics and distinction of the invention is the system which takes the physical, structural and/or other potential characteristics of the vehicle (mobile entity), upon entry to the secured area such as a parking or storage facility (lot, garage, etc.), or a private, government or military facility or base, or a cargo/freight/container/trailer facility/area and such information is stored in data form in a system which may then be accessed immediately or at various times in the future by authorized users of such data which can be examined, converted, manipulated and/or transferred in potentially a broad variety of ways/methods as needed and ultimately to release and display the vehicle characteristics which where identified and stored in any form (typically digital or analog) as appropriate for the applications.
Specific vehicle entry and exit dates, times, frequencies (relative to use of the parking/storage facility), and possible any vehicle occupants, whether one or more, would be data/details potentially available for study and/or analysis potentially for a wide variety of applications, if so authorized. Particular and relatively non-ordinary vehicle features, as well as any onboard signature, might be analyzable by those organizations having authority and/or licensed to access, handle and review such data and/or details.
Unique vehicle and/or occupant characteristics may be captured during each entry into and exit from any secured area. One purpose, along with many others, might be to explore presence, patterns, frequencies, etc. of possibly significant and/or related events. Database details, captured over time, could be analyzed for characteristics potentially related to location and/or entry-exit security and/or evolving activities or events either deserving proactive intervention before negative, possibly disastrous situations can occur or for reconstruction of past circumstances.
One example of the basic sequence of events, relative to the use of the security system for vehicles secured (parked/stored) in a controlled area, and in particular an area for taking in vehicles for parking where a level of security exists, is provided in the sequential description below: Entry Sequence:
1) A vehicle enters one parking access entry lane of possibly a plurality of entry locations and potentially concurrent with a plurality of vehicles each entering one of the other entry lanes;
2) An Onboard Identity (OI) code in the vehicle and/or alternatively camera(s), sensor(s) or other forms of detection and recordation device(s), are positioned such that information relative to the entering vehicle including, if appropriate operator/occupant information perhaps in the form of a photograph, as well as details such as vehicle manufacturer, model, color, size, license plate, VIN, etc. all or some of which may be detected and recorded thereby creating a vehicle Characteristics Identity (CI).
3) A security monitoring/tracking system is provided which may be in the form of a computer and/or processor or a similarly functional system of components which causes the creation of a random and/or encoded sequence of characters, bar codes, numbers, letters. et. al., as the vehicle “Signature” (SI) based or either the OI or CI or both;
4) A physical ticket/tag (receipt of any type) containing the time and date of entry of the vehicle plus an encoding of the vehicle SI is dispensed or issued from a dispensing device. The encoded SI may be in a text form or any alternative forms such as but not limited to bar-code, magnetic strip, encryption or a variety of other forms. The operator of the entering vehicle may then progress to a parking region/area/location and secure the vehicle. Exit Sequence
5) The method and system used to ultimately create the stored vehicle signature SI at entry is similarly located at an appropriate position for exiting the secured area. The controlled area may be a secured parking, storage, or staging area but could also be as diverse as a region of vehicle entry and exit on a substantially continuous basis-for example entry into or onto a monitorable road/route/area or a private, government, military facility, even where exiting may occur very soon there from;
6) A system, such as computer and/or processor or similarly functioning system of components, is used for matching the exit created SI to the initial SI developed and recorded/stored at the entry position. If such an SI match is found, the SI is provided to the system/terminal at the exit point which might also have an attendant operator, security guard, or electronic checkout terminal, depending on the controls being exercised. In a secured parking application, the vehicle operator/driver will likely possess the T/T (or equivalent), received at the time of vehicle entry, which is encoded with the system recorded entry SI. If the vehicle operator provided T/T information matches the SI received from the match-finding system, an ACCEPT signal will be displayed or audibly communicated. The original facility entry time and date, as indicated by the T/T are then used to compute any fees, if applicable, based upon the exit time and date. Such fees are accepted by the attendant or checkout terminal facility in any established/acceptable payment form. If a diverse vehicle entry and exit situation exists per #5 above, a unique exit process will be utilized to align with the parameters present and controls required;
7) If an SI mismatch of any kind is found, the attendant and/or the checkout terminal conveys a REJECT notice along with a routine required of the vehicle operator to resolve the mismatch by proving such factors as ownership, damage to the T/T, proof of a relationship between the vehicle operator at entry and the vehicle operator at exiting, possession of the T/T created and dispensed at entry, etc.; and
8) If all efforts fail to resolve the problems associated with justifying an ACCEPT condition, i.e., a FAIL condition repeats/persists, the vehicle is detained and security methods (defined by the responsible facility or entity authority) are applied.
FIGS. 1 through 3 describe examples of the presently known applications or uses of the method, apparatus and system of this invention. FIG. 1 provides a start to finish complete overview of one example of the entire entry/exit process. FIG. 2 expands the Entry Related Activities to convey a mobile entity either with an Onboard Identity (OI) or sensing of discrete, specific physical characteristics to collectively create a Characteristics Identity (CI). Either the OI or CI can be utilized to create a system-stored entity Signature (SI) associated with a Ticket/Tag encoded and delivered to the entity owner/operator for later reclaiming of the specific entity.
Similarly, FIG. 3 expands the sequential activities associated with later reclaiming of an entity after some time period that the entity has been secured (controlled and/or protected) in a defined area or zone. The key process attributes in this figure relate to the level of security provided through both a re-identification via the Onboard Identity (OI) or the collective identity characteristics associated with a multi-sourced Characteristics Identity (CI). The encoded Ticket/Tag is the key to legitimizing the holder's right to reclaim the stored entity/vehicle at this later date. Any Ticket/Tag whose encoding does not align with the electronically filed Signature (SI) will be rejected automatically and the entity will remain secured.
Included below in text form are examples of the invention having incorporated therein different forms of vehicle sensor systems to read/interpret an Onboard Identity (OI) device then system generate and store a unique vehicle “Signature” (SI). In one example there is a reference to “Vehicle Signature” which means a unique set of identity details associated with the OI create a unique system defined SI which is then encoded/encrypted for this particular vehicle and dispensed to the vehicle operator in some Ticket/Tag (T/T) removable claim check. The OI is a vehicle-unique identity tag or label, either installed at the factory or at a later date, which contains a unique code or fingerprint assigned to that vehicle. The OI can be in a broad variety of forms such as an infrared light energy pattern, a detectable barcode tag readable from outside the vehicle, or a coded frequency and signal transmitter which is detected by the entry and exit systems for creating the SI defined for the entering vehicle. The sensor is disclosed as an infrared system, or an RF system (radio frequency form).
In another example of the invention described below, there is a reference to “Vehicle Characteristics” which mean that structural, physical, color, manufacturer, model, year, license tag, VIN and/or other discrete physical characteristics associated with the particular entering vehicle are detected as a unique collective composite defining a Characteristics Identity (CI) for the vehicle. This CI fingerprint is system stored and a unique SI is generated, along with the dispensing of a T/T as described above. The sensor system may be a plurality of camera systems, (digital video, magnetic video or any other form of image capture).
Parking Security—Vehicle Signature Tied to Parking Ticket/Tag
1) Vehicle contains a unique (stationary, permanent or portable) identity device. 2) When entering parking area, unique identity device is read/sensed by area equipment (optical, RF, infrared, et. al). 3) Vehicle identity may be “system” stored/filed, at driver's discretion. 4) System ties unique identity to a vehicle identifier, e.g., random no, swipe card code, et. al., retained/removed by the vehicle driver. 5) Unique vehicle identifier provided to owner on transportable medium, e.g., parking ticket, etc.
With Pre-Sensing Prior to Exit Check-Out
6) When vehicle exiting parking area, unique identity device is read/sensed by area equipment (optical, RF, infrared, et. al):
a) At a pre-sensing point between parked location and check-out; or b) At (staffed or un-staffed) checkout point.
7) Unique identifier number/mark/code system associated with original dispensed ticket number. 8) At checkout point, parking ticket or other physical device with unique identifier(s) is validated against the unique vehicle related identifier. Code on transportable medium (ticket) is compared to (optical, RF, infrared, et. al) re-scan of vehicle's unique (stationary or permanent) identity device read/sensed by area equipment. 9) Unique identifier number/mark/code system associated with dispensed ticket number:
a) If unique ticket encoded identity matches unique vehicle identity, exiting proceeds. b) If (all) required identifier(s) do not match, area methods (gate or similar) detain vehicle pending resolution.
Without Pre-Sensing Prior to Exit Check-Out
6) When vehicle approaching parking area exit check-out, the vehicle unique identity device is read/sensed by area equipment (optical, RF, infrared, et. al). 7) At checkout point, parking ticket or other physical device with unique identifier(s) is validated against the unique vehicle related identifier. Code on transportable medium (ticket) is compared to (optical, RF, infrared, et. al) re-scan of vehicle's unique (stationary or permanent) identity device read/sensed by area equipment. 8) Unique identifier number/mark/code system associated with dispensed ticket number:
a) If unique ticket encoded identity matches unique vehicle identity, exiting proceeds. b) If (all) required identifies do not match, area methods (gate or similar) detain vehicle pending resolution.
Parking Security—Vehicle Characteristics Tied to Parking Ticket/Tag
1) Area mounted (stationary/permanent) optical system(s) capture unique characteristics for each vehicle upon entering a controlled area/zone. 2) Distinguishing characteristics may include but are not be limited to: a) License plate with/without sufficient surrounding vehicle details to tie plate details to a unique vehicle type, e.g., model, color, etc.; &/or, b) Vehicle VIN number; &/or, c) Vehicle occupant(s) Vehicle. 3) A unique vehicle identity is established using distinguishing characteristics (per #2) and can be stored/filed by the system identity capabilities for future use. 4) System ties unique identity to a vehicle identifier, e.g., random no, swipe card code, et. al., retained/removed by the vehicle driver. 5) Unique vehicle identifier provided to owner on transportable medium, e.g., parking ticket, etc.
With Pre-Sensing Prior to Exit Check-Out
6) When vehicle exiting parking area, unique vehicle (identity) characteristics are read/sensed by area optical sensors:
a) At a pre-sensing point between parked location and check-out; or b) At (staffed or un-staffed) checkout point.
7) Sensed unique (identity) characteristics are system associated with original dispensed ticket number. 8) At checkout point, parking ticket or other physical device with unique identifier is validated against the unique vehicle identity characteristics. Code on transportable medium (ticket) is compared to optical re-scan of vehicle's unique identity characteristics read/sensed by area equipment. 9) Unique identifier number/mark/code system associated with dispensed ticket number:
a) If unique ticket encoded identity matches unique vehicle identity, exiting proceeds. b) If (all) required identifier(s) do not match, area methods (gate or similar) detain vehicle pending resolution.
Without Pre-Sensing Prior to Exit Check-Out
6) When vehicle approaching parking area exit check-out, the vehicle unique characteristics are read/sensed by area optical equipment. 7) At checkout point, parking ticket or other physical device with unique identifier(s) is validated against the unique vehicle related identity. Code on transportable medium (ticket) is compared to optical re-scan of vehicle's unique identity read/sensed by area equipment. 8) Unique identifier number/mark/code system associated with dispensed ticket number:
a) If unique ticket encoded identity matches unique vehicle identity, exiting proceeds. b) If (all) required identities do not match, area methods (gate or similar) detain vehicle pending resolution.
In both the OI and CI based identity systems, the same system/methods utilized at vehicle entry are repeated during the exiting activities and the OI and/or CI identity characteristics are duplicated to confirm the same, identical vehicle is now departing. The originally dispensed T/T from vehicle entry must be produced and system validated to confirm the surrendered encoded T/T was the one dispensed when this vehicle entered since it will contain the system defined SI unique to this vehicle. Any applicable fees associated with the parking duration of the secured vehicle are dealt with in the conventional fashion, though likely a premium rate would be associated with the additional security services.
It is thought that the present invention, the means and method and the system for securing (protecting or controlling) areas and/or acquiring additional income potential from a “secured” parking facility, or for providing security to areas which are openly accessible or accessed by vehicles with or without specific access authorization or for recognizing vehicles having an Onboard Identity (OI) as a component part of the vehicle, or alternatively utilizing a variety of discrete vehicle-specific physical characteristic for collectively defining a Characteristic Identity (CI), either of which can be utilized by a site system for defining a site unique Signature (SI) for each vehicle at its entry and during it's on-site presence, and at vehicle exiting the repetition of the same OI and/or CI identification done at vehicle entry to validate authorized departure against the system-stored SI from entry, plus validating the authorized operator of said vehicle via the operator surrendering the encode Ticket/Tag received at vehicle entry which is validated against the system stored SI encoding of same at entry, completing the entire security process of this invention which is totally disclosed herein, recognizing there exists potential variations of the characteristics of the elements of the system of the invention based on site, system and application variations. There currently exists a broad array of features and variations in the available sensing devices, devices for creating identity codes, ticket/tag production methods, as well as system recognition of acceptance criteria at vehicle entry and/or exit.
Variations of the disclosure principles can be applied to both monitor location and control movement and/or flow of a broad variety of entities. Examples include but are not limited to:
1) Should an onboard identity device eventually become a mandatory, integral component built into all vehicle's onboard computerized control systems, a broad variety of monitoring could be exercised, if allowed by law;
2) Expanding the micro (parking lot) example above to a military base or industrial complex monitored at entry and departure points for limited or total movement of select or all vehicles;
3) Restricting or closely monitoring access to and/or movement within controlled areas such as military or industrial complexes so:
a) unauthorized movement can be detected and or controlled;
b) only vehicles having permanent Onboard Identity (OI) would be allowed to enter and depart without being security cleared;
c) vehicles without OI would be issued a temporary identity device which would allow the vehicle's movements on-site to be closely monitored and/or tracked but might set off an alarm if tampered with while on site;
4) Depending on the extent and interaction of monitoring locations, complete sensing networks could potentially be established to monitor and/or control vehicle access to zones of varying sizes, even to the extent of applying these aspects to municipalities where discrete sensing features might be included at major traffic artery points, bridges, tunnels, et. al. Such monitoring could be capable of utilizing either the OI or CI systems or both to detect specific vehicles which may potentially pass through monitoring points such as:
a) fleeing suspects in known vehicles where the OI was identified via a trail through the license plate; or, a CI signature is established through an eye witness vehicle description;
b) vehicles identified as used by individuals or factions potentially presenting security risks:
c) monitoring the movement of persons of interest during evolving criminal cases:
5) Fleets of container/freight vehicles with OI devices could be point-to-point monitored automatically to determine, define and/or provide:
a) specific arrival and departure details for automatic system tracking and related projections:
b) compliance with defined schedules, perhaps along progressive delivery routes;
c) movement and staging of specific containers throughout warehouse staging/transfer points;
d) system monitoring on-time dependent shipments to verify schedules are or will be met, e.g., all expedited containers are onboard a transport device, e.g., truck, before its departure;
e) arrival time at client locations for staging 1 sequencing the client's dock utilization as well as utilization of the shipments contents by the client;
f) automatic system notification to all delivery points should an in-transit delay occur;
g) maintenance schedules of equipment with an OI by monitoring total activity over time:
6) Securable transport devices such as containers, enclosed pallets, cartons crates. et. al. could utilize these concepts for:
a) tracking, monitoring and controlling container movement:
b) tracking conservation of sealed, secured contents within such containers if the sealing device utilized is similarly equipped with sensing devices having OI like features which could emit an alert if seal tampering occurs; and
c) OI devices could be system tracked on a site (dock, storage, staging area, etc.) for inventory control and location applications.
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A method and system for securing, protecting and controlling defined areas by managing access points for entering and exiting vehicles or mobile entities, and matching entering vehicle or mobile entity identification information with exiting identification information. This may include obtaining and storing a unique onboard signature and/or physical characteristics from entering vehicles or mobile entities for matching with the identity information obtained from exiting vehicles or mobile entities. In addition a paper or electronic Ticket/Tag may be encoded with the entering identification information and issued to an agent of the entering vehicle or mobile entity for later presentation at exiting, whereby a three-way matching of exiting, entering, and Ticket/Tag information must be satisfied for the vehicle or mobile entity to be released from the controlled area.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation of application Ser. No. 09/674,922, filed Nov. 8, 2000, which is incorporated herein by reference in it entirety.
BACKGROUND OF THE INVENTION
This invention relates to a method and apparatus for treating a semi-conductor substrate in particular, although not exclusively, a semi-conductor wafer.
In our earlier co-pending Patent Application WO094/01885, the contents of which are incorporated herein by reference, we describe a planarisation technique in which a liquid short-chain polymer is formed on a semi-conductor wafer by reacting silane with hydrogen peroxide. WO098/08249, which is also incorporated herein by reference, describes a method of treating a semi-conductor substrate including reacting an organo-silane compound of the general formula C x H y —Si n H a and a compound containing peroxide bonding to provide a short-chain polymer layer on the substrate.
The prior art processes generally comprise the step of depositing the layer between two layers of high quality plasma enhanced silicon dioxide layers, i.e. a base layer and a capping layer. These provide adhesion and moisture barriers. The deposited layer includes water which is removed in a controlled manner and baked at a high temperature to “cure” the layer, thus completing the process of depositing a hard layer. It has been considered important to control the diffusion of water to avoid cracking, as described in WO095/31823, which is also incorporated herein by reference. This careful control and the provision of a capping layer are both time-consuming and expensive.
SUMMARY OF THE INVENTION
According to a first aspect of the present invention, there is provided a method of treating a semi-conductor substrate comprising the steps of:
(a) depositing on the substrate a polymer layer; and (b) heating the substrate in the absence of oxygen prior to the deposition of any further layer to substantially remove O—H bonds from the polymer and substantially cure the layer.
The method may further comprise the step of positioning the substrate in a chamber prior to step (a), and the reactants may be introduced into the chamber in a gaseous or vapour state.
According to a further aspect of the present invention, there is provided a method of treating a semi-conductor substrate comprising the steps of:
(a) positioning the substrate in a chamber; (b) introducing into the chamber in the gaseous or vapour state a silicon-containing compound and a further compound containing peroxide bonding, and reacting the silicon-containing compound with the further compound to provide on said substrate a polymer layer; and (c) heating the substrate in the absence of oxygen prior to the deposition of any further layer to substantially remove O—H bonds from the polymer and substantially cure the layer.
The heating may be substantially by radiative means.
Thus, the method of the present invention provides a substrate which does not require a capping layer or a subsequent furnace bake, thereby significantly improving the throughput of the equipment, and providing equipment savings and process simplification. In addition, the present invention provides a low dielectric constant (low k) layer.
Preferably, the substrate is a wafer, for example a silicon wafer. However, any suitable substrate could be used, for example a glass or quartz panel. The method may be carried out with or without an underlayer on the substrate, for example a silicon dioxide underlayer.
Preferably, the silicon-containing compound may be of the general formula (C x H y ) b Si n H a , for example C x H y —Si n H a , or (C x H y O) b Si n H a or (C x H y O) b Si n H m (C r H s ) p . The values of x, y, n, m, r, s, p a and b, can be any suitable values. Thus, the silicon-containing compound is preferably a silane or a siloxane. The silicon-containing compound is preferably a methyl silane.
The O—H bonds may be removed in the form of water.
When used, the radiative means may comprise an infra red component in the radiation spectrum.
In a preferred embodiment, the heating is carried out at a maximum temperature at or above 400° C., and preferably at a maximum temperature at or below 450° C. However, lower temperatures could be envisaged depending on the particular polymer layer deposited. Whilst silane source layers may blister when processed, variations to the process (eg lower temperatures or slower heat-up times) may yield satisfactory drying and curing of a silane source layer. The heating may be provided by any suitable source, for example one or more lamp sources or a black body emitter. The heating may be provided from a source providing infra-red heat. Alternatively, the source for providing the heating may provide UV heat. A UV source may be particularly useful in Shallow Trench Isolation applications. In one particular embodiment, the source for providing the heating comprises one or more tungsten halogen lamps, which may act through quartz. Alternatively, the heating may be provided by a platen or chuck on which the substrate is placed, for example a hot metal chuck and in this case longer process times may be required. The substrate may or may not be clamped to the chuck, although preferably no clamping pressure is applied.
The heating step may take about eight seconds to reach the maximum temperature.
The heating step may be performed by a rapid rise in layer temperature, for example by applying high power to the lamp heat source, for approximately 8 seconds followed by lower power for up to five minutes, and preferably for more than one minute. Even more preferably the heating step is performed for about three minutes. Prior to the heating step, the substrate may be transferred to a second chamber in which the heating step is performed.
The heating step may be carried out in a non super saturated environment and is preferably carried out at below atmospheric pressure. In one embodiment, the pressure is preferably about 40 mT, which may be maintained by continually pumping the chamber in which the heating step is performed. This pressure is generally as a result of background pressure of evolved gases.
Preferably the thickness of the polymer layer and base layer (where applicable) is less than 1.5 μm, even more preferably the thickness is less than 1.3 μm and it may be less than 1.25 μm. These are typical thicknesses which may avoid cracking of the substrate.
The thickness of the polymer layer is preferably between 5,000 Å and 10,000 Å, although any appropriate thickness may be used.
Whilst the substrate may be positioned in any convenient orientation, it has been found that it is particularly convenient to position the substrate such that the polymer layer is on the upward face, with heating from a source placed below the substrate. This is not to say that the layer is shielded from radiation as there may be reflection from internal chamber surfaces and the substrate itself may be transmissive to at least parts of the radiated spectrum.
According to a further aspect of the present invention, there is provided an apparatus for implementing the method described above comprising means for depositing on the substrate a polymer layer, and means for heating the substrate in the absence of oxygen prior to the deposition of any further layer.
According to a further aspect of the present invention, there is provided an apparatus for implementing the method described above, the apparatus comprising:
(a) a chamber having means for introducing therein a silicon-containing compound and a further compound containing peroxide bonding, and platen means for supporting a substrate; and (b) a chamber having means for heating the substrate in the absence of oxygen prior to the deposition of any further layer.
The chambers used in (a) and (b) may be the same or different.
In a preferred embodiment, the apparatus may further comprise means for sustaining a non super saturated environment, preferably at below atmospheric pressure.
Radiative means for heating may be provided.
The radiative means may comprise an infra red component in the radiation spectrum.
Although the invention has been defined above, it is to be understood that it includes any inventive combination of the features set out above or in the following description.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention may be performed in various ways and specific embodiments will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 shows a graph of FTIR absorbance against wave numbers for the as deposited film, after the treatment of the invention and after 9 nights in ambient atmosphere after this treatment;
FIG. 2 shows the change in dielectric constant over time of a 8″ wafer which is subject to three minutes heat treatment under vacuum and has a 7,000 Å layer on the substrate;
FIG. 3 shows the change in capacitance by way of comparison against the thickness of the layer on the substrate for 6″ and 8″ wafers at 450° C. for different treatments;
FIG. 4 shows the change in capacitance against thickness of the layer on the substrate for 6″ wafers at 450° C. for one minute;
FIG. 5 shows the change in capacitance against thickness of the layer on the substrate for 6″ wafers at 450° C. for three minutes;
FIG. 6 shows the change in capacitance against the thickness of the layer on the substrate for 8″ wafers at 450° C. for one minute;
FIG. 7 shows the change in capacitance against the thickness of the layer on the substrate for 8″ wafers at 450° C. for three minutes;
FIG. 8 shows the relative emissive power of a lamp with wavelength and temperature;
FIG. 9 shows the peak wavelength of a lamp with filament temperature;
FIG. 10 in contrast shows the change in capacitance against the thickness of the layer on the substrate for 8″ wafers when treated in an oven at 400° C. for 30 minutes where oxygen was present;
FIG. 11 shows FTIR spectra for a polymer layer treated at 500° C. in an oven in a dry nitrogen ambient and thus generally regarded as oxygen free;
FIG. 12 shows a perspective view of an apparatus according to the present invention;
FIG. 13 shows a cross-section view of an apparatus according to the present invention; and
FIG. 14 shows an alternative cross-section view of an apparatus according to the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
As can be seen from FIG. 1 , water is removed by the treatment of the invention and is not reabsorbed (wavenumbers around 3000 to 3600) and it can also be seen that SiO—H bonds are removed by this heat treatment (wavenumber 920).
In FIGS. 1 to 7 , all the results are based on the methyl silane deposition described below. Polymer thicknesses vary between 5,000 Å and 10,000 Å. Reabsorption of water into the film is best measured by observing the change in capacitance values over time. In FIG. 3 , the bottom point shows the results after 24 hours and the top point shows the results after 6 days for the same wafer. Two runs were performed for each treatment, labelled A and B. 0-6-3 refers to the thickness in thousands of Angstroms of the base layer, polymer layer and capping layer respectively. Also included are results obtained by the capping and oven heating of a 6000 Å polymer layer. The capping layer of plasma deposited silicon dioxide has been plasma etched away leaving approximately 5200 Å of polymer layer which has then been similarly exposed to atmosphere.
As can be, seen from FIG. 10 , which shows the results of treatment in an oven as distinct from the radiative treatment of the invention, there are large changes in capacitance as a result of oxygen being present during the heat treatment.
In FIG. 11 are shown the results (as an expansion around wavenumber 3000 to highlight water) for a polymer layer treated at 500° C. in an oven with a dry nitrogen ambient, that is without the radiative treatment of the invention. The lines show data for the layer:
a) as deposited (no heat treatment); b) immediately after heat treatment, showing that the water is removed; and c) 3 and 7 nights later showing that water has been reabsorbed.
Significant reabsorption of water occurs with oven treatment, which is avoided by the radiative treatment of the invention. It is believed that this is because the dry nitrogen ambient is not completely free of oxygen even though it is generally regarded as such and would generally be described as a “nitrogen bake” or “nitrogen anneal”.
In addition to the results shown in FIG. 3 , reabsorption results were tested by etching a cap layer of a full sequence of methyl silane deposition (ie. having been deposited over a silicon dioxide underlayer with a silicon dioxide capping layer over the silicon dioxide deposited layer) where 7000 Å of methyl source film and 3000 Å of plasma deposited silicon oxide capping layer with or without a 1000 Å base layer of plasma deposited silicon dioxide were used. The capping layer was dry etched off in a Plasma chamber using the following parameters: 1400 mT, 750/250 sccm CF 4 /O 2 , 1 kW, 25 secs. The layer left was about 5,500 Å thick. Results gave a change in capacitance of 2.1% and 5.7% in 24 hours. After 6 nights change in capacitance between 2.3% and 6.9%. No differences were found between base and baseless wafers.
To arrive at the graphical results shown in FIGS. 1-7 , 10 and 11 methyl silane deposition (D120) was carried out in accordance with the present invention, the conditions for which were as follows:
80 sccm methyl silane were reacted in a chamber with 0.75 g/m hydrogen peroxide under a pressure of 1,000 mTorr to form a polymeric layer on a silicon substrate. The substrate was then transferred out of the vacuum to the atmosphere where it was left for a significant period of time (for example days or even weeks). It was then transferred back into a vacuum where heat is applied, in accordance with the present invention. In the specific embodiment, the heater comprises multiple tungsten halogen theatre spotlights (i.e. a broad band white light) through quartz (which provides a cut-off at around 400 nm). The data for such a lamp is shown in FIGS. 8 and 9 .
The atmospheric exposure between deposition and heat treatment was a necessary consequence of not having the heat treatment station on the methyl deposition system. This does not appear to be detrimental. It is the exclusion of oxygen (preferably below 100 parts per million) during the heat treatment step that is critical in ensuring that the layer does not subsequently absorb water.
Results of the method of the invention were compared to a standard method involving methyl silane and a caping layer. The standard method includes transferring the wafer under vacuum from the platen at 0° C. to an aluminium platen at 350° C. and plasma depositing a capping layer of approximately 3,000 Å before air exposure and subsequent furnace bake.
The present invention avoids the need for the capping layer and convection furnace bake. It has been found that for methyl silane materials it is preferable to use a vacuum heat process to harden and complete the process without the necessity for a plasma deposited capping layer. Whilst the Applicant does not wish to be restricted hereby, this is considered to be as a result of the exclusion of oxygen during the heat treatment.
In terms of the process time (ie. the time of the final heating step in the vacuum), a three minute process provides suitable reabsorption results but good results are also obtained using other process times. In terms of the process pressure, the pressure is preferably set at approximately 40 mTorr during the processes with continual pumping.
FIGS. 12 to 14 show an apparatus generally at 1 in accordance with the invention. FIG. 14 is a more detailed view than the schematic view in FIG. 13 . The apparatus 1 comprises a chamber 2 into which the reactants may be passed in the absence of oxygen and within which a wafer 3 may be positioned through a wafer loading slot 4 . A door module is shown at 5 . The chamber comprises a polished lid 6 on which is arranged a manometer 7 , an atmospheric sensor 8 and an ionisation gauge tube 9 . The wafer 3 is positioned on a support 10 and is lifted by a bellows wafer lift assembly 11 . A quartz chamber base 12 is provided. Beneath the chamber 2 is a lamp unit 13 within which is positioned a heating lamp 14 which may be, for example, a tungsten halogen lamp. The lamp 14 is substantially housed within a parabolic reflector 15 . Positioned beneath the lamp unit 13 is a cooling fan 16 . The chamber 2 may be heated by an electrical heating jacket 17 .
Connected to the chamber 2 is a turbo pump assembly (not shown) connected via an automatic pressure control 19 and a valve 20 .
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This invention relates to a method of treating a semiconductor wafer and in particular, but not exclusively, to planarisation. The method consists of depositing a liquid short-chain polymer formed from a silicon containing bas or vapour. Subsequently water and OH are removed and the layer is stabilised.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to closures for paperboard cartons and more particularly to means for providing a tight seal in the closure to prevent the contents thereof from sifting out through the seams.
2. Description of the Prior Art
Paperboard cartons are an inexpensive and convenient method for storage, shipment and display of almost any type of article. Where the contents of the carton, however, are to be finely divided, such as powders, granulated materials, or any small particulate matter such as seeds, it is necessary that the end closures of the carton be tightly sealable. This seal is necessary not only to keep the contents from sifting out through the seams, but to prevent insects from attaining entry into the box. A common method of overcoming these problems is to provide the carton with a bag enclosure within the carton or a tight paper overwrap label over an unprinted paperboard package. This, of course, adds to the complexity of the equipment, the cost of the packaging, as well as the shipping weight.
Embossing the end flaps so that they lie in closer relationship is also common, as described in U.S. Pat. No. 3,003,677 which is assigned to the assignee of the present application. None of these solutions is entirely desirable nor completely satisfactory in its operation.
SUMMARY OF THE INVENTION
A configuration of bands of adhesive applied to the end flaps of a paperboard carton where two of the end flaps in opposed relationship substantially cover the area of the end of the carton. One of these flaps is folded into position with the other flaps outwardly opened and two bands of adhesive are placed along each side of this first folded flap and onto the adjacent secondary flaps which are then folded into position creating a tight seal over which the second large flap is folded which may have a band of adhesive placed thereon to give even further protection.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a carton having an end closure embodying the present invention shown in perspective with one side flap folded into position and the adhesive bands applied thereto prior to folding the other flaps;
FIG. 2 is a blank shown in plan view which is adapted to be folded into a carton having an end closure which may be adaptable to use with the present invention;
FIG. 3 is a perspective view of an end of a carton similar to that shown in FIG. 1 with one of the secondary flaps folded into position;
FIG. 4 is a top plan view of the carton closure shown in FIG. 1 with the secondary flaps folded in position and the fourth flap yet open;
FIG. 5 is a top plan view of the carton closure shown in FIGS. 1, 3 and 4 with the flaps in final folded position;
FIG. 6 is a side elevational section view of a portion of the closure shown in FIG. 5 taken along section lines 6--6;
FIG. 7 is a side elevational section view taken along section line 7--7 in FIG. 5.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
This invention has particular application to those cartons which will be used for containing powders or other finely divided material which have a tendency to sift out through the crevices between the end closure flaps in a conventional carton closure. Cartons designed to contain this type of material generally have at least two flaps which are formed in size an amount substantially equal to the cross sectional area of the end of the carton. The blank in FIG. 2 is for a standard rectangular wrap-around style carton having four side panels adapted to be connected in rectangular common tubular relation. The blank is made from a substantially rectangular sheet of foldable paperboard or similar sheet-like material and has four side panels 10, 11, 12 and 13 defined by three parallel fold lines 20, 21 and 22. The particular blank as shown has a manufacturer's joint flap 23 connected along one edge by a fourth fold line 24. For convenience only one end of the carton will be detailed and as can be seen at the top of the blank there are four closure flaps hingedly attached to the adjacent panels along a hinge line perpendicular to the first mentioned fold lines and designated as 30. The closure flaps are formed so that they will be in opposed relationship in the folded configuration of the container, and two of these opposed flaps, 40 and 41 are attached to the side panels 11 and 13 respectively and are formed in height substantially equal to the width of the opposed side panels 10 and 12, so that in folded relationship they will cover substantially the entire surface area of the end of the carton. The remaining two flaps 43 and 44 are hingedly attached to the side panels 10 and 12 and in the particular configuration shown are not of such a size as to cover the entire end of the carton. When the opposing side panels are substantially different in width as in the blank of FIG. 2, to have these remaining flaps sized at about the same height as the flaps 40 and 41 facilitates manufacture thereof, but if a carton is designed which is substantially square in cross section then it becomes more feasible to have all four closure flaps substantially equal to the open end area of the carton.
As can be seen in the Figures, the particular carton shown has end flaps embossed to permit them to lie in closer relationship than standard flaps, such as described in the U.S. Pat. No. 3,003,677 issued Oct. 10, 1961. The necessity for embossing these flaps depends in large part on the thickness of the paperboard to be used as well as the particle size of the material to be contained within the carton. The dashed lines and the opposed flaps 40 and 41 in FIG. 2 are intended to represent the borders of the embossed areas and are seen better in FIGS. 1 and 3.
FIG. 1 shows the opposed carton panels 10, 11, 12 and 13 in folded tubular relationship and illustrates the appropriate position of the flaps when the adhesive is to be applied. One of the two opposed flaps 40 and 41 which substantially cover the end of the carton is folded inwardly to cover the end of the carton and the remaining flaps are opened outwardly into the same plane exposing their inwardly foldable surfaces. In FIG. 1 flap 41 is shown folded inwardly first since it is embossed to accommodate the remaining flaps 43 and 44 on its outer surface, but if no embossing is used then either flaps 41 or 40 may be folded first. The reason for having the flaps in this position is that the bands of adhesive shown as 60, 61 and 62 may be applied in straight lines by using conventional equipment for dispensing adhesive and may be dispensed by moving the carton linearly underneath the equipment. The adhesive used may be any of those well known in the art including cold resin and hot-melt types. The first band of adhesive 60 is dispensed along the outer edge of the first folded flap 41 juxtaposed with the hinge line of the second opposed flap 40 and is spread in a continuous band onto the adjacent areas of the remaining flaps 43 and 44. The purpose of this band of adhesive is to seal the opening along that edge where the first flap 41 meets the hinge line 30 at the top of the side panel 11. The second continuous band of adhesive is applied along the opposite edge of the first folded panel 41 along the hinge line which connects flap 41 to the side panel 13. The band is likewise extended onto the adjacent areas of the remaining flaps 43 and 44.
It can be seen in FIG. 3 that the remaining flaps 43 and 44 are folded inwardly and a complete seal results around the top of the carton by virtue of the two bands of adhesive 60 and 61 which extend the length of the side panels 11 and 13 and which, because the remaining flaps 43 and 44 are folded inwardly plug up the joint or crack which results in the corner and also where the hinge line 30 joins the two flaps 43 and 44 to the side panels 10 and 12 of the carton. The second opposed flap 40 may be folded downward and attached by conventional means, but additional sealing properties and closure rigidity will be obtained if the third band of adhesive 62 is applied along the inwardly foldable surface of the second flap 40 in such a position that in its final folded position the third band of adhesive 62 will be located between the first and second bands of adhesive 60 and 61.
FIGS. 4 and 5 illustrate a plan view of the carton shown in FIG. 3 after the two flaps 43 and 44 are in folded position but with the second folded flap 40 in the outward position. FIG. 5 as previously mentioned shows a plan view of the final folded container with only the outward flap 40 visible and the three bands of adhesive 60, 61 and 62 shown in dash lines, illustrating how the third band of adhesive 62 in the final folded position lies between the first two bands 60 and 61.
FIGS. 6 and 7 are two views through the sections indicated in FIG. 5 which help to illustrate how the present invention provides adequate sealing of the carton. FIG. 6 shows how the adhesive band 60 squeezes to completely seal off the crack resulting when the flap 41 is folded down and shows how in the corner of the carton the double thickness of adhesive which results when flap 44 is folded inwardly provides even more adhesive to form a bead which completely seals any openings to prevent sifting of the material contents from within the carton. Likewise the bands of adhesive 61 and 60 seal off the crevices, and in the particular configuration shown, in which the remaining flaps 43 and 44 do not extend completely to the midpoint of the carton, the two bands of adhesive 60 and 61 also help to seal the second opposed flap 40 into position on top of the earlier folded flaps. FIG. 6 differs from FIG. 7 in that it is taken through a section where there is embossing to accommodate the remaining flap 44 between the two larger opposed flaps 40 and 41. FIG. 7, on the other hand, is a section through the center showing only the relationship of the two opposed flaps 40 and 41.
In accordance with the Patent Statutes, I have described the principles of construction and operation of my improvement in CARTON SEALING; and while I have endeavored to set forth the best embodiment thereof, I desire to have it understood that obvious changes may be made within the scope of the following claims without departing from the spirit of my invention.
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Sealed carton closure and method for making same particularly adapted for paperboard cartons having inwardly foldable flaps where the carton is designed to contain material which is subject to sifting or leaking out of the carton. A first end closure flap is folded into position over the entire opening and a band of adhesive is placed across each side of the first flap with the adhesive extending onto the adjacent flaps which are then folded inwardly to create a sealed end with a fourth flap folded on top of the first folded flaps. A third band of adhesive may be used to hold the fourth flap in position and provide additional sealing qualities.
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The present invention relates to new and useful anionic hydrogels which are stable three dimensional copolymer networks, having good water permeability and mechanical properties, and are obtained by simultaneous copolymerization and cross-linking, in the presence of a polymerization catalyst, of a mixture of (a) a heterocyclic N-vinyl monomer, preferably an N-vinyl lactam, (b) a polymerizable ethylenically unsaturated monomer containing acid groups such as carboxylic acid groups, sulfonic acid groups or acidic sulfate ester or phosphate ester groups, and (c) a crosslinking agent, such as a glycol diacrylate or dimethacrylate or divinyl benzene, etc.; and also, preferably, (d) at least one acrylic monomer capable of polymerizing to a very high molecular weight; there may also be present (e) other polymerizable ethylenically unsaturated monomers, which are copolymerizable with components (a), (b), (c) and (d).
BACKGROUND OF THE INVENTION
In my U.S. Pat. No. 3,532,679, issued Oct. 6, 1970, and entitled Hydrogels from Cross-linked Polymers of N-Vinyl Lactams and Alkyl Acrylates, I have described certain neutral hydrogels obtained by simultaneous polymerization and cross-linking of a mixture of an N-vinyl lactam, and alkyl acrylates. In my copending application Ser. No. 385,275 filed July 27, 1973, now U.S. Pat. No. 3,878,175 issued Apr. 15, 1975, I have described an improvement on my said patent, wherein a solution of the monomers in a hydrophobic solvent is simultaneously polymerized and cross-linked; whereby a highly absorbent, spongy, polymeric, neutral hydrogel is obtained.
I have now found that such N-vinyl lactam or other heterocyclic N-vinyl monomer based hydrogels can be modified, by incorporating an anionic monomer in the mixture of monomers being simultaneously polymerized and cross-linked, so that a hydrogel having anionic functionality, and thus new and useful properties, is obtained.
A number of synthetic polymeric materials, which contain acidic groups which impart anionic functionality thereto are known in the art; possibly the most widely available and best known of such anionic synthetic resins, are the cation exchange resins available under such trade-names as Amberlite, Dowex, Permutit and Zeocarb. In genereal the so-called "weak" cation exchange resins contain carboxylic groups while the so-called "strong" cation exchange resins contain sulfonic groups. However, such cation exchange resins are not hydrogels.
As disclosed in my prior U.S. Pat. No. 3,532,679, supra, various cross-linked hydrogels are known in the art. However, practically all of these known hydrogels are neutral hydrogels and are not inoic in character. While in U.S. Pat. No. 3,689,634, issued Sept. 5, 1972 to Kliment, Vacik, Majkus and Wichterle, entitled Protracted Activity Oral Hydrogel Bead; there is a broad suggestion that "it is also possible to replace the non-ionizable cross-linked hydrogels by physically similar hydrogels containing also ionizable groups"; the only examples of ionic hydrogels disclosed in this patent are: "A porous hydrogel capable of exchanging cations prepared by copolymerizing a mixture of 35 parts of methacrylic acid, and 30 parts of a 25 percent aqueous solution of maleic anhydride," disclosed in Example 8 at the top of column 8 of the patent; and "A copolymer prepared from 97 parts of ethylene glycol monomethacrylate, 2 parts of methacrylic acid and 1 percent of ethylene glycol bis-methacrylate by suspension polymerization in a concentrated, aqueous solution of sodium chloride, using 0.05 parts of diisopropyl percarbonate as a polymerization initiator," disclosed in Example 9 at the middle of column 8 of the patent. These prior art ionic hydrogels are obviously substantially different from those of the present invention; inter alia, the prior art hydrogels contain no N-vinyl lactam, or other N-vinyl heterocyclic monomer units and thus are structurally different from those of the present invention, and would be lacking in properties attributable to such N-vinyl lactam etc. units.
Other ionic synthetic polymeric materials which are known in the prior art, are the self-stabilizing polymer latices obtained by emulsion polymerization techniques in which a copolymerizable surfactant is used as an emulsifier in the preparation of the aqueous emulsion of monomer(s) to be polymerized. In the course of the polymerization, these copolymerizable surfactants copolymerized with the monomer or mixture of other monomers being polymerized and become an integral part of the resulting polymer so that the polymeric material so obtained contains ionic (acidic) groups. As examples of acidic, ionic, copolymerizable surfactants which have been so used may be mentioned the polymerizable α-methylene carboxylic acid esters (e.g., the acrylic and methacrylic acid esters) of hydroxyalkane sulfonic acids such as those disclosed in U.S. Pat. No. 3,024,211 and 3,033,833 both to Le Fevre and Sheetz and U.S. Pat. No. 3,617,368 to Gibbs and Wessling; also the sulfate esters of hydroxyalkyl acrylates and methacrylates disclosed in my U.S. Pat. No. 3,839,393 issued Oct. 1, 1974; also the phosphate esters of hydroxyalkyl acrylates and methacrylates disclosed in my copending application Ser. No. 321,229, filed Jan. 5, 1973, now U.S. Pat. No. 3,855,364; and the sulfates of polymerizable ethylenically unsaturated alcohols and their alkylene oxide adducts disclosed in my application Ser. No. 321,228, filed Jan. 5, 1973, now U.S. Pat. No. 3,875,202. Such copolymerizable surfactants are also used to impart hydrophilic properties to the resulting polymer, to improve the receptivity of the resulting polymer to basic dyes and other purposes more fully described in the above patents; however, none of the polymers heretofore produced by their use have, to the best of my knowledge, been in the form of hydrogels.
One of the outstanding advantages of the hydrogels of the present invention which contain anionic groups, as compared with the non-hydrogel form of anionic polymeric materials heretofore obtained by the use of anionic copolymerizable monomers, such as those mentioned above which contain carboxylic, sulfonic or sulfate groups, is that the hydrogel form of the anionic polymers of the present invention permits and assures much more intimate contact between the anionic groups of the anionic polymeric hydrogel and any basic material which it is desired to combine or complex therewith. In the presence of water the anionic hydrogels of the present invention are quite permeable and swollen. Due to this swelling the water, and any basic material dissolved or dispersed therein, of an aqueous medium with which these anionic hydrogels are used, or come in contact with during use, can readily diffuse or be transported throughout the hydrogel. As a result, combination or complexing of basic materials with the anionic groups of the polymeric hydrogel can and does take place throughout the hydrogel in contrast for example, with the essentially surface action in the case of cation exchange resins. This swelling also increases the distance between the anionic groups of the hydrogel and this is also conductive to more complete reaction. Thus basic materials can be combined or complexed much more efficiently and completely with the anionic groups of the anionic polymeric hydrogels of the present invention; and, conversely, basic materials which are complexed or otherwise combined with the anionic groups of the anionic polymeric hydrogels of this invention may be more efficiently released therefrom and transferred to an aqueous medium with which they are used; especially in comparison with corresponding ion exchange resins.
OBJECTS OF THE INVENTION
It is, therefore, an object of the present invention to provide a new class anionic polymeric materials, containing acidic groups, in the form of hydrogels having new and useful properties.
It is a further object of this invention to provide methods of making this new class of anionic hydrogels.
It is a further object of this invention to provide new and useful compositions and processes containing and/or utilizing the novel anionic hydrogels of this invention.
Other and further objects will be apparent as the present description progresses.
DETAILED DESCRIPTION OF THE INVENTION
As previously stated, the novel anionic hydrogels of this invention are obtained by simultaneous catalytic polymerization and cross-linking of a mixture of:
a. a heterocyclic N-vinyl monomer;
b. an ethylenically unsaturated monomer, which is copolymerizable with component (a) and which contains an acid group in its molecular structure; and
c. a cross-linking agent;
I also prefer to include in the monomer mixture:
d. at least one acrylic monomer capable of polymerizing to a very high molecular weight;
there may also be present in the monomer mixture:
e. other polymerizable mono-ethylenically unsaturated monomers, which are copolymerizable with components (a), (b), (c) and (d).
Component (a)
The heterocyclic N-vinyl monomer, used as component (a) above, may be N-vinyl imidazole, having the formula: ##STR1## but I prefer to employ a heterocyclic N-vinyl monomer containing a carbonyl function adjacent to the nitrogen in its heterocyclic moiety and represented by the following formula: ##STR2## wherein R represents a divalent aliphatic group, preferably alkylene, containing a linear chain of 3 to 5 atoms necessary to make up the 5 to 7 membered heterocyclic ring.
I particularly prefer N-vinyl-2-pyrrolidone or other N-vinyl lactams such as N-vinyl-2-piperidone or N-vinyl-E-caprolactam. These N-vinyl lactams may be substituted in the lactam ring by one or more lower alkyl groups such as methyl, ethyl or propyl. As examples of other heterocyclic N-vinyl-monomers, which may be used as component (a), either alone or in admixture with each other or in admixture with one or more N-vinyl lactams, may be mentioned: N-vinyl succinimide, N-vinyl diglycoylimide, N-vinyl glutarimide, N-vinyl-3-morpholinone, N-vinyl-5-methyl-3-morpholinone, N-vinyl imidazole, etc.
Component (b)
As component (b) -- an ethylenically unsaturated monomer, which is copolymerizable with component (a) and which contains an acid group in its molecular structure -- I may use any of the usual polymerizable or copolymerizable ethylenically unsaturated acids commonly used in vinyl and related polymerizations to produce polymers having acid functionality. These include such ethylenically unsaturated carboxylic acids as: acrylic acid, methacrylic acid, maleic acid, maleic anhydride, fumaric acid, itaconic acid, ethyl acid maleate, citraconic acid, crotonic acid, aconitic acid, cinnamic acid, and similar unsaturated carboxylic acids. However, I particularly prefer to employ as component (b) an ethylenically unsaturated polymerizable monomer in which the acid group is a sulfonic acid group, a sulfate ester group or a phosphate ester group. Such acidic monomers are employed in the form of the free acid or of their salts, e.g. as their ammonium or alkali metal, e.g. sodium or potassium, salts.
As examples of suitable polymerizable monomers which contain sulfonic acid groups may be mentioned; vinyl sulfonic acid, styrene sulfonic acid (e.g. p-vinylbenzenesulfonic acid), acrylamidoaryl sulfonic acids and acrylamidoalkyl sulfonic acids of the formula: ##STR3## wherein: R is hydrogen or alkyl of 1 to 4 carbon atoms, R' is an aryl or alkyl group having at least 2 carbon atoms separating N from S.
A number of specific polymerizable acrylamido aryl sulfonic acids and acrylamidoalkyl sulfonic acids of this type are disclosed in U.S. Pat. No. 2,983,712 issued May 9, 1961 to Wilkinson; I particularly prefer the acrylamidoalkyl sulfonic acids disclosed in said patent and also U.S. Pat. Nos. 3,332,904 issued July 25, 1967 to LaCombe and Miller; 3,478,091 issued Nov. 11, 1969 to Murfia and Miller; and 3,506,707 issued Apr. 14, 1970 to Miller and Murfia, such as 2-acrylamido-2-methylpropane-1-sulfonic acid.
Another preferred class of monomers containing sulfonic acid groups are the so-called copolymerizable surfactants which are esters of polymerizable α-methylene carboxylic acids, especially acrylic or methacrylic acid, with hydroxyalkane sulfonic acids, especially isethionic acids, and which may be represented by the formula: ##STR4## wherein, R is hydrogen, halogen (e.g., chlorine or bromine), or an organic radical, preferably alkylene of from 1 to about 6 carbon atoms; Q is a bivalent organic radical having its valence bonds on two different carbon atoms, preferably alkylene of from 2 to about 6 carbon atoms; and M is a cation, e.g. ammonium, amino, alkali metal or alkaline earth metal etc. A number of such esters, of α-methylene carboxylic acids with hydroxyalkane sulfonic acids, which may be used as component (b) are disclosed in U.S. Pat. No. 3,024,221 issued Mar. 6, 1962 to Le Fevre and Sheetz; and as examples thereof may be mentioned 2-sulfoethyl acrylate, 2-sulfoethyl methacrylate, 2-sulfoethyl-α-ethylacrylate, 2-sulfoethyl-α-propylacrylate, 2-sulfoethyl-α-butylacrylate, 2-sulfoethyl-α-cyclohexylacrylate, 2-sulfoethyl-α-chloroacrylate, 3-sulfo-1-propyl acrylate, 3-sulfo-1-propyl methacrylate, 3-sulfo-1-butyl acrylate, 4-sulfo-1-butyl acrylate, 4-sulfo-1-butyl methacrylate, ar-sulfophenyl acrylate, ar-sulfophenyl methacrylate, and other like esters disclosed in said U.S. Pat. No. 3,024,221. Also, the glycidyl acrylate sulfonate and glycidyl methacrylate sulfonate disclosed in U.S. Pat. No. 3,541,059 issued Nov. 17, 1970 to Shaper and in Japanese Pat. No. 73 32,089 issued Oct. 4, 1973 to Nippon Oils and Fats Co., Ltd.
As copolymerizable surfactants in which the acid group is a sulfate or phosphate group I particularly prefer the sulfate esters of hydroxyalkyl acrylates or methacrylates (or the hydroxyalkyl esters of similar α-methylene carboxylic acids) disclosed in my U.S. Pat. No. 3,839,393 issued Oct. 1, 1974; the sulfate esters of polymerizable ethylenically unsaturated alcohols and their alkylene oxide adducts disclosed in my prior application Ser. No. 321,228 filed Jan. 5, 1973; and the phosphate esters of hydroxyalkyl acrylates and methacrylates disclosed in my prior U.S. Pat. No. 3,855,364 issued Dec. 17, 1974. These types of sulfate or phosphate ester monomers may be represented, respectively, by the following general formulas: ##STR5## In the forgoing formulas 5, 6 and 7: R represents hydrogen or alkyl of 1 to about 6 carbons;
R" represents hydrogen, methyl or phenyl;
R' represents hydrogen, or alkyl, preferably methyl or ethyl
m represents an integer of from 1 to about 18;
n represents an integer, preferably of from 1 to about 4;
x represents an integer of from 1 to 2;
y represents an integer of from 1 to 2, provided that the sum of x and y is 2; and
M represents a cation, i.e. hydrogen, ammonium, amino, alkali metal or alkaline earth metal.
As examples of specific materials of these types may be mentioned; 2-sulfatoethyl acrylate, 2-sulfatoethyl methacrylate, 2-sulfatopropyl acrylate, 2-sulfatopropyl methacrylate, 2-sulfatobutyl acrylate, 2-sulfatobutyl methacrylate, ω-sulfatodiethyleneglycol monoacrylate, ω-sulfatodiethylenglycol monomethacrylate, ω-sulfatotriethyleneglycol monoacrylate, ω-sulfato-triethyleneglycol monomethacrylate and other analogous materials disclosed in said U.S. Pat. No. 3,839,393.
Also the sulfates of such monoethylenically unsaturated alcohols as allyl alcohol, allyl carbinol, methallyl alcohol, hexen-1ol-6, octen-1-ol-8, undecenyl alcohol (undecen-1-ol-11), dodecen-1-ol-12, tetradecen-1-ol-14, cinnamyl alcohol and the like, and the sulfates of alkylene oxide adducts (ethylene oxide, propylene oxide or butylene oxide adducts) of the forgoing unsaturated alcohols, such as 2-hydroxyethyl ether of allyl alcohol, 2-hydroxyethyl ether of butene-1-ol-4,2-hydroxyethyl ether of undecenyl alcohol, the monoallyl ethers of di-, tri- and tetra-ethylene glycol, the monohexenyl ethers of di-, tri-, and tetra-ethylene glycol, the mono-undecenyl ethers of di-, tri-, and tetraethylene glycol, the adduct of allyl alcohol with 3 molar proportions of ethylene oxide, the adduct of cinnamyl alcohol with 3 molar proportions of propylene oxide, the adduct of cinnamyl alcohol with a mixture of three molar proportions of ethylene oxide and two molar proportions of propylene oxide, the adducts of undecenyl alcohol with 12, 20, 35 and 50 molar proportions of ethylene oxide, the adduct of allyl alcohol with six molar proportions of 1,2-butylene oxide and 12 molar proportions of ethylene oxide and analogous materials disclosed in said application Ser. No. 321,228, now U.S. Pat. No. 3,875,202.
As examples of ethylenically unsaturated monomers containing phosphate ester groups may be mentioned the phosphate monoesters and phosphate di-esters of hydroxyalkyl acrylates and methacrylates, especially the mixtures of a major amount of the phosphate monoester and a minor amount of the phosphate diester of such hydroxyalkyl acrylates and methacrylates; as specific examples thereof may be mentioned the mixtures of about 55% to about 75% of the phosphates monosters of mono-, di- and/or tri-ethylene glycol monoacrylates and monomethacrylates with about 10% to about 20% of the phosphate diesters of the mono-, di-, and tri-ethylene glycol monoacrylates and monomethacrylates, and analogous materials of Formula 6 above, disclosed in my application Ser. No. 321,229, now U.S. Pat. No. 3,855,364 issued Dec. 17, 1974, and analogous unsaturated monomers containing phosphate ester groups.
Component (c) (c)
As the cross-linking agent, component (c), I particularly prefer the alkylene glycol diacrylates or dimethacrylates and the polyalkylene glycol diacrylates and dimethacrylates, represented by the formula: ##STR6## wherein, R represents hydrogen or alkyl of 1 to 4 carbon atoms, and
A represents alkylene of from 2 to about 10 carbons or a polyglycol ether group of the formula ##STR7## in which R 1 represents hydrogen, methyl or ethyl, and
n is an integer of from 1 to about 20.
As examples thereof may be mentioned: ethylene glycol diacrylate, ethylene glycol dimethacrylate, propylene glycol diacrylate, propylene glycol dimethacrylate, diethylene glycol diacrylate, diethyleneglycol dimethacrylate, triethylene glycol diacrylate, triethylene glycol dimethacrylate, tetraethylene glycol diacrylate, tetraethylene glycol dimethacrylate, pentaethylene glycol diacrylate, pentaethylene glycol dimethacrylate, hexamethylene glycol diacrylate, hexamethylene glycol dimethacrylate, and mixtures of the going There may also be used such cross-linking agents as divinylbenzene, divinyl ether, divinyl toluene, diallyl tartrate, diallyl maleate, divinyl tartrate, N,N'-methylene-bis-acrylamide, and the like.
While I have obtained valuable anionic hydrogels by the use of a mixture of only monomer components (a), (b) and (c); I have found that the anionic hydrogels so produced may contain an appreciable amount of relatively low molecular weight polymers (i.e. polymers of a molecular weight of from 10,000 to 50,000) and may be somewhat less physically strong than desired, possibly due to the water solubility of their low molecular weight polymer content. While anionic hydrogels containing such relatively low molecular weight polymers may be preferred for certain applications, I have found that for most applications polymeric materials which are relatively free of such low molecular weight polymers are to be preferred. In order to assure the production of anionic hydrogels having the most desirable properties for most applications, I preferably include in the mixture of monomers, which is simultaneously polymerized and cross-linked, as component (d) of such mixture, an appreciable amount of at least one acrylic monomer capable of polymerizing to a very high molecular weight (100,000 or higher). The presence of such a component (d) serves to substantially increase the average molecular weight of the resulting anionic polymeric hydrogel and to minimize or eliminate the amount of relatively low molecular weight anionic polymers present therein.
Component (d)
Component (d) -- an acrylic monomer capable of polymerizing to a very high molecular weight -- is any acrylic monomer which may be represented by the following general formula: ##STR8## wherein: R and R' each represents hydrogen, or lower alkyl of 1 to about 4 carbon atoms; and
R" represents hydroxyl, alkoxy or hydroxyalkoxy or,
when n is 0 (zero), R" may also represent --NH 2 or ##STR9## and n represents an integer (including 0) of from 0 to about 20.
As component (d), I particularly prefer acrylamides such as acrylamide, N-(1,1-dimethyl-3-oxobutyl) acrylamide also called diacetone acrylamide (described in U.S. Pat. No. 3,497,467, issued Feb. 24, 1970 to Coleman) and methacrylamide; hydroxyalkyl acrylates and methacrylates such as glyceryl monoacrylate and glyceryl monomethacrylate; and glycol monoacrylates and glycol monomethacrylates or monohydroxy (and monoalkoxy) polyalkylene glycol acrylates and methacrylates. Such hydroxy alkyl acrylates and methacrylates may be considered as the alkylene oxide adducts of acrylic or methacrylic acid with alkylene oxides, as they are generally produced by the reaction of one molar proportion of acrylic or methacrylic acid with one or several molar proportions of a lower alkylene oxide, such as ethylene oxide, propylene oxide or 1,2-butylene oxide. As examples of specific hydroxy alkyl acrylates and methacrylates and of monohydroxy (and monoalkoxy) polyalkylene glycol monoacrylates and monomethacrylates of Formula 9, which may be used as component (d), may be mentioned: hydroxyethyl acrylate, hydroxyethyl methacrylate, diethylene glycol monoacrylate, diethylene glycol monomethacrylate, triethylene glycol monoacrylate, triethylene glycol monomethacrylate, methoxyethylene glycol acrylate or methacrylate, methoxy polyethylene glycol acrylate or methacrylate, ethoxy ethylene glycol acrylate or methacrylate, ethoxy polyethylene glycol acrylate or methacrylate, butoxy ethylene glycol acrylate or methacrylate, 2-hydroxy propyl acrylate or methacrylate, 2-hydroxy butyl acrylate or methacrylate, polypropylene glycol acrylate or methacrylate, polybutyleneglycol acrylate and methacrylate and analogous hydroxyalkyl acrylates or methacrylates and monohydroxy (and monoalkoxy) polyalkylene glycol acrylates and methacrylates.
Such acrylic monomers as acrylonitrile, methacrylonitrile and alkyl acrylates amd methacrylates are also quite effective for increasing the molecular weight of the polymeric hydrogels of the present invention and may be used as component (d) if desired. It is quite possible and entirely feasible to use a mixture of several acrylic monomers as component (d) and from a cost standpoint it is frequently advantageous to use a mixture of say acrylamide with one or more of, the somewhat more expensive, hydroxyalkyl acrylates or methacrylates. The alkyl acrylates and methacrylates, especially the lower alkyl acrylates and methacrylates, are also less expensive than the hydroxyalkyl acrylates and methacrylates; so that, where cost is a controlling or important factor, it is often advantageous to replace all or part of the preferred hydroxyalkyl acrylates or methacrylates listed above with an alkyl acrylate or methacrylate. As examples of specific alkyl acrylates and methacrylates, which may be used as component (d), either alone or in admixture with each other or in admixture with one or more of the preferred hydroxyalkyl acrylates or methacrylates, listed above, may be mentioned: methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, lauryl acrylate, lauryl methacrylate, etc. The lower members of this series are preferred, because of greater reactivity and because larger percentages can be incorporated into the copolymer without substantially reducing the percent swelling and hydrophilic characteristics of the copolymers.
Component (e)
As previously mentioned, if desired there may also be used, as component (e), other monoethylenically unsaturated monomers which are copolymerizable with components (a), (b), (c) and (d) in the mixture of monomers subjected tp simultaneous polymerization and cross-linking. As examples of specific monomers which may be used as component (e) may be mentioned: vinyl acetate, vinyl propionate, vinyl butyrate, vinyl chloride, vinylidene chloride, vinyl methyl ketone, styrene, methoxystryrene, monochlorostyrene, ar-methylstyrene, ar-ethylstyrene, α, ar-dimethylstyrene, ar, ar-dimethylstyrene, vinylnaphthalene, vinyl benzoate, ethyl vinyl ether, n-butyl vinyl ether, isobutyl vinyl ether and the like.
The fact that the anionic polymers of the present invention are hydrogels, as distinguished from a solid resinous structure, I attribute primarily to the amount of component (a) -- the heterocyclic N-vinyl monomer component -- used in their preparation or, when a component (d) is used and is a water-soluble acrylic monomer such as a hydroxyalkyl acrylate or methacrylate or a monohydroxy polyglycol monoacrylate or monomethacrylate, to the combined amount of component (a) and such component (d) used in their preparation; and only secondarily to the amount of cross-linking agent, component (c), which is used. Within the proportions, specified below, of monomer components, the amount of cross-linking agent appears to effect primarily the degree of water swellability of the hydrogel. With any given recipe the swellability (expressed as water content at equillibrium at 25° C., in percent by weight), of the hydrogel ultimately obtained, decreases as the amount of cross-linking agent employed therein is increased; and is thus inversely proportional to the amount of cross-linker used.
The anionic character of the ionic hydrogels of the present invention is attributable to the amount of component (b) -- the monoethylenically unsaturated monomer containing an acid group -- used in their preparation; and the amount of cationic materials which may be combined or complexed with them is directly proportional to the amount of component (b) used. Thus the particular application contemplated for the anionic hydrogel and the amount of cationic material, with which it is desirable that they be able to combine, will primarily determine the amount of component (b) to be used.
Considerable variation is possible in the relative amount of each of the forgoing monomer components (a), (b), (c), (d) and (e) which is used and an anionic polymeric hydrogel is obtained when the mixture of such monomer components which is subjected to simultaneous polymerization and cross-linking is composed of:
______________________________________% by weight(based on total weightof all monomercomponents used) Component______________________________________about 20% to about 95% (a)- the heterocyclic N-vinyl monomer. -about 50% to about (b)- the monethylenically unsaturated0.05% monomer which contains an acid group in its molecular structure.about 0.2% to about 12% (c)- the cross-linking agent.0% to about 50% (d)- the acrylic monomer capable of polymerizing to a very high molecular weight.0% to about 30% (e)- a.polymerizable monoethylenically unsaturated monomer.______________________________________
It will be understood that while the primary function served by component (d), when it is used, is to increase the molecular weight of the anionic hydrogel which is ultimately obtained and to minimize or eliminate the presence of relatively low molecular polymers in the ultimate hydrogel; component (d) can also be considered as an extender or partial replacement of the heterocyclic N-vinyl monomer, component (a). When a component (d) is used, the total amount of component (d) which is used in any particular recipe should not exceed the amount of component (a) used in the same recipe. However the total amount of both component (a) and component (d) which is used should not exceed the maximum amount of component (a) (95% by weight of the total monomers) specified above. This can also be expressed "(a)≧(d) and (a) + (d) = about 40% to about 95% by weight of the total weight of all monomers used".
Polymerization and Cross-Linking
The simultaneous polymerization and cross-linking to make the hydrogels of the present invention may be carried out by various techniques known in the art. Thus the polymerization and cross-linking may be effected by bulk polymerization of a mixture of the several monomer components (a), (b), (c), and (d) and (e) if desired, in the proportions given above, in the presence of a free radical polymerization catalyst such as any of the well known inorganic or organic peroxides, azobisisobutyronitrile, etc. polymerization catalysts.
Such catalysts may be employed in the range of about 0.05 to about 4% of the total monomers. The preferred amount of catalyst is about 0.1 to about 2.0% of the monomer components. Typical catalysts include MEK peroxide (methyl ethyl ketone peroxide), lauroyl peroxide, t-butyl-peroctoate, benzoyl peroxide, isopropyl percarbonate, cumene hydroperoxide, dicumyl peroxide, azobisiso-butyronitrile, potassium persulfate, potassium peroxide, etc. Irradiation, as by ultraviolet light or gamma rays, also can be used to catalyze the polymerization and cross-linking.
The polymerization and cross-linking may be effected at temperatures in the range of 20° C. to 100° C. or somewhat higher, preferably in the range of 35° C. to about 60° C., until most of the polymerization is effected, followed by a post-cure at about 100° C. to about 125° C. for about an hour.
Advantageously, the polymerization and cross-linking may be effected by the use of a casting technique of the type described in my said U.S. Pat. No. 3,532,679 in which a mixture of the monomer components, catalyst and, if desired, a mold release agent is deaerated, as by the application of vacuum until air bubbles no longer rise to the surface, poured into a suitable mold, such as a polymerization tray or cell, which is then sealed and held at a suitable temperature, as by placing in a circulating air oven or heating bath, until a hard polymer is obtained. The hard polymer so obtained may be further cured by heating to a somewhat higher temperature, than that used for the polymerization, such as 100° C. to 125° C. for about an hour. The cell is then opened and the cured polymer removed therefrom. The mold may be in the shape of the desired product or the solid polymer may be fabricated, after curing, into the desired shape; e.g., it may be ground into a powder or cut into the desired shape. Such polymerization and cross-linking may also be carried out in the manner described in my said copending application Ser. No. 385,275, filed July 27, 1973, now U.S. Pat. No. 3,878,175 issued Apr. 15, 1975, wherein a solution of the several monomer components in an inert, nonpolar hydrophobic liquid such as silicone liquid, hexane, octane, mineral oil, toluene, xylene, etc. is simultaneously polymerized and cross-linked; whereby the polymer can ultimately be obtained in a porous or spongy or foamy form.
It will also be understood that the simultaneous polymerization and cross-linking may be effected, employing solvent polymerization techniques, in the presence of water-soluble solvents in which the monomer components (a), (b), (c), (d) and (e) are soluble. Such solvents include the lower aliphatic alcohols such as methanol, ethanol, propanol and isopropanol; acetone, dioxane, ethylene glycol, glycol esters or ethers etc. By such procedures the polymer is obtained in the form of an organogel from which the organic solvent may be removed by washing with water or by distillation or evaporation.
The polymer so obtained by casting may then be immersed in water and thereby gradually swollen into a hydrogel. In the case of polymers produced in a casting technique involving the use of either a hydrophobic or water soluble solvent and which thus still contain the solvent, the solvent is displaced by the water during the immersion. Such displacement of the solvent by the water may be speeded up by kneading or squeezing the polymer during the swelling, as by passing it between squeeze rollers. The swelling in water is continued until equilibrium is reached, or until a hydrogel containing the desired amounts of water is reached. The anionic hydrogels so obtained are soft pliable materials which can be reacted with cationic materials.
It will be appreciated that polymeric products having a predetermined shape may be obtained by the use of molds of the desired shape. Thus, a product having a definite curved shape may be obtained by casting between a pair of curved glass sheets. Rods may be obtained by casting and curing in glass or plastic (e.g. nylon or polyethylene) tubes. Hollow tubes can be cast between two concentrically disposed glass tubes or by centrifugal casting procedures under polymerization conditions.
Further details of the present invention are illustrated in the specific examples which follow of preferred embodiments thereof. In these examples the polymeric anionic hydrogels were prepared employing a conventional type casting cell prepared by inserting a soft and flexible, three-sixteenth inch thick, vinyl gasket between two pieces of 8 × 12 × 1/4 inch polished plate glass, the gasket being positioned about one inch from the edge of the glass sheets. The glass plates were then clamped with spring type clamps, such as one inch binder clips or spring loaded clamps. The size of the cell is not critical but will depend on the size of cast sheet desired and any size limitations of the oven or heating bath to be employed. For laboratory preparations I have found glass sizes of up to 16 × 16 inches to be convenient. The thickness of the gasket should be about 20-30% greater than the desired thickness of the final cast sheet and round, square or rectangular gaskets with sides or diameter of from about 0.8 inch to about 0.5 inch may be used to control sheet thickness. Rods may conveniently be cast in sealed glass, nylon, polyethylene, etc. tubing of approximately 1/2 inch diameter and 12 - 18 inches long.
The casting mixture consisting of monomers, catalyst, mold release agent or other additives if desired, was deaerated by application of vacuum until air bubbles no longer rose to the surface. The deaerated casting mixture is then poured into the casting cell which is then sealed and placed horizontally on a shelf in a circulating air oven equipped with constant temperature control. Unless otherwise specified it was kept in this oven at 50°-55° C. until substantially polymerized, usually in 18-48 hours. The temperature is then raised gradually (over 2-4 hours) to approximately 100° C., and polymerization completed during 1 to 3 hours at 100°-125° C. The mold was allowed to cool to room temperature, the clips removed, and the mold pried open to release a clear, colorless and rigid sheet.
EXAMPLE 1.
To a 1 liter, three neck flask equipped with a mechanical stirrer, and vacuum line there was charged the following reactants:
80 grams of N-vinyl-2-pyrrolidone,
20 grams of methacrylic acid
0.6 grams of tetraethylene glycol dimethacrylate and
2.0 grams of MEK peroxide*, 11.5% active oxygen.
The flask was thoroughly purged with nitrogen while stirring to effect solution and vacuum was then applied until gas bubbles no longer rose to the surface. The solution in the flask was then poured into a laboratory size glass casting cell consisting of two pieces of 8 × 12 inch plate glass, 1/4 inch thick, clamped to three-sixteenth inch thick soft vinyl gasket. The sealed mold was laid on the shelf in a circulating air oven equipped with constant temperature control and maintained at 60° C. for 40 hours. Polymerization and cross-linking was then continued by gradually raising the temperature of the oven to 100° C. over a three hour period and holding at this temperature for one hour. The mold was removed from the oven and allowed to cool to room temperature, the clamps removed and the mold then pried open. The thus obtained clear, rigid, hard sheet was then immersed in water and allowed to swell until equilibrium had been reached. The thus obtained hydrogel was a tough pliable material, the water content of which, at equilibrium at 25° C., was 24.6% by weight.
EXAMPLE 2.
The procedure of Example 1 was repeated using the following charge of reactants:
60.0 grams of N-vinyl pyrrolidone,
20.0 grams of acrylamide,
20.0 grams of methylmethacrylate,
1.0 grams of the sodium salt of the sulfate ester of 2-hydroxylethyl methacrylate,
0.6 grams of tetraethylene glycol dimethacrylate and
2.0 grams of MEK peroxide, 11.5% active oxygen.
The resilient pliable hydrogel ultimately obtained had a water content of 72% by weight at equilibrium at 25° C.
EXAMPLE 3.
The procedure of Example 1 was again repeated using the following charge of reactants:
60.0 grams of N-vinyl pyrrolidone,
20.0 grams of acrylamide,
20.0 grams of methyl acrylate,
1.0 grams of the ammonium salt of the sulfate ester of 2-hydroxyethylacrylate,
0.6 grams of tetraethylene glycol dimethacrylate and
2.0 grams of MEK peroxide, 11.5% active oxygen
The soft pliable rubbery hydrogel ultimately obtained had a water content of 82% by weight at equilibrium at 25° C.
The hydrogels of Examples 2 and 3 were washed with acidified water, containing sufficient HCl to give a pH of 1.0, to convert the sulfate ester groups of the sulfate ester of 2-hydroxyethyl methacrylate units of the copolymer to their free acid form and then given a final wash with distilled water to remove any HCl remaining therein. Samples of the thus treated hydrogels of Examples 2 and 3 and also of the hydrogel of Example 1 readily react with basic materials when placed in aqueous solutions or dispersion of the basic material.
It will be understood that the forgoing examples are illustrative only of the present invention and are not to be interpreted as limiting the invention. A wide variety of anionic hydrogels can readily be produced employing other specific reactants of the type heretofor specified in proportions within the ranges specified. Additional specific recipes useful for the production of anionic hydrogels by the process of Example 1 or analogous procedures are given immediately below in tabular form.
Table 1.__________________________________________________________________________COMPONENT PARTS BY WEIGHT Recipe 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16__________________________________________________________________________(a) N-vinyl pyrrolidene 65 40 55 50 25 30 50 90 70 65 50 50 55 50 N-vinyl piperidone 55 50 Beta sulfoethyl methacrylate 5 25 NH.sub.4 -salt of 2-hydroxyethyl methacrylate sulfate 10 30 50 10 10 Glycidyl methacrylate sulfonate 5 20 Sodium salt of 2-methacrylamido-2-methylpropane- 5 101-sulfonic acid(b) 2-hydroxyethyl methacrylate phosphate 10 10 10 Methacrylic acid 10 Acrylic acid 20(c) Triethylene glycol dimethacrylate .8 .4 Polyethylene glycol (400) dimethacrylate .5 .4 .4 .4 .3 .35 .8 .9 .6 .25 .15 .4 .3 .4 .7 Acrylamide 15 15 5 Methacrylamide 10 Hydroxyethyl methacrylate 20 20 35 20 25 30 20 40 40 35 40 20(d) Hydroxyethyl acrylate 35 Hydroxypropyl acetate 20 Methyl acrylate 15 10 Methyl methacrylate 30 Water 20 15 50 20 40 Catalyst MEK peroxide, 11.5% active oxygen 1.4 1 1 1.5 1 1 1 .9 Isopropyl percarbonate .1 .4 .05 .2 .4 .1 Potassium persulfate .3 .25 Azo bis isobutyronitrile .6 .25 2 .8__________________________________________________________________________
The thus obtained anionic hydrogels of the present invention have a variety of applications in the arts. As previously stated they may readily be combined, by reaction or complexing, with materials having a basic (cationic) group or groups. Such combination with basic materials may be effected by immersing or swelling the anionic hydrogel in an aqueous solution or suspension of the basic material which it is desired to combine or complex therewith. Alternatively, if the basic material to be combined or complexed with the hydrogel is stable at the conditions used for polymerization and cross-linking, such basic material may be added to the mixture of monomers prior to or during polymerization and cross-linking so that the anionic hydrogel is obtained directly in the form of its desired reaction product or complex with such basic material. Alternately one can first form the salt or complex of component (b) -- the ethylenically unsaturated monomer which contains an acid group in its molecular structure -- with such stable basic (cationic) materials and use such salt or complex as component (b) in the simultaneous polymerization and cross-linking.
Thus the anionic hydrogels of the present invention, in the form of their alkali metal salts may be used as cation exchangers in a manner analogous to cation exchange resins. The anionic hydrogels of this invention are particularly valuable for combination with basic biologically active materials as basic agricultural chemicals, basic drugs and other pharmaceuticals, hormones, enzymes and basic cosmetic materials.
As examples of agricultural chemicals which may be combined with the anionic hydrogels of this invention and which are slowly released therefrom under conditions of use, when applied to plants, may be mentioned: such herbicides as Atrazine; 2,4-dichloro-6-(o-chloroanilino)-s-triazine; 2-(ethylamino)-4-(isopropylamino)-6-(methylthio)-s-triazine; 2-chloro-4-ethylamino-6-isopropylamino-s-triazine; 2-t.butylamino-4-ethylamino-6-thio-s-triazine; 2-4-bis(3-methoxypropyl)-amino -6-methylthio-s-triazine; 2-4-bis(isopropylamino)-6-methoxy-s-triazine; 2-4-bis(isopropylamino)-6-methylthio-s-triazine; and 2-chloro-4,6-bis(isopropylamino)-s-triazine.
As examples of basic pharmaceutical products which may be combined with the anionic hydrogels of this invention may be mentioned: Atropine; Atropine-N-oxide; dextroamphetamine; racemic amphetamine; ephedrine; d-desoxyephedrin; homatropine; imipramine; chlorophenoxamine; phenylephrine; phenmetrazine; phenazocine; procaine; strychnine; etc. Also such basic narcotics as codein and morphine; anticonvulsants as: diphenyl hydantoin; and pro-diphenyl hydantoin: ##STR10## described in C&EN of September 22, 1974, page 26; basic antibiotics as: streptomycin; tetracycline; terramycine and aureomycine; basic hormones as insulin and thyroxin; basic vitamins as Vitamin K 6 ; basic tranquilizers as: promazine; chlorpromazine; dichlorpromazine; prochlorperazine; trifluoperazine; thiopropazate; chlorprothixene; and reserpine; basic antihistamines as: diphenylhydramine; pyrilamine; pheniramine; and chlorpheniramine; such glaucoma treating agents as: carbachol; epinephrine or its dipivalate ester known as pro-epinephrine (described in C&EN, September 22, 1974, page 26); and pilocarpine; also basic narcotic antagonists as: cyclazocine (2-cyclopropylmethyl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan or, using Chem. Abstracts nomenclature and numbering, 1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3 benzazocin-8-ol) and other narcotic antagonists of the general formula (Chem. Abstracts numbering): ##STR11## wherein: R is a hydrocarbon radical about 4.4 A in length. e.g., propyl, butyl, cyclopropylmethyl or allyl;
R' and R 2 are lower alkyl groups (R' may be H) which may be joined to form a cyclohexane ring;
and R 3 is H, alkyl or acyl, i.e., the substituent in 8-position is a hydroxyl, ether or ester group;
described by S. Archer, N. F. Albertson and A. K. Pierson in a paper paper entitled "Structure-activity relationships in the opioid antagonists" appearing at pages 25-29 of Agonist Antagonist Actions Narcotic Analg. Drugs, Proc. Int. Symp. 1971, edited by H. W. Kosterlitz and published 1973 by Univ. Park Press, Baltimore, Md.; and by F. M. Robinson in Chapter 3. Analgesics and Narcotic Antagonists at pages 31-38 of Annu. Rep. Med. Chem. 1972.
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Novel anionic hydrogels, containing acidic groups, and their preparation are described. These novel hydrogels are stable, three-dimensional polymer networks, having good water permeability and mechanical properties. They are obtained by simultaneous polymerization and cross-linking, in the presence of a polymerization catalyst, such as an organic peroxide, azobisisobutyronitrile or other free radical polymerization catalyst, of a mixture of (a) a heterocyclic monomer preferably an N-vinyl lactam, (b) a polymerizable acidic monomer, such as acrylic or methacrylic acid, sulfo-ethyl methacrylate or a sulfated or phosphated derivative of a hydroxyalkyl- acrylate or methacrylate and (c) a cross-linking agent, such as a glycol or polyglycol diacrylate or dimethacrylate and also, preferably, (d) at least one acrylic monomer capable of polymerizing to a very molecular weight, such as hydroxyethyl- or hydroxypropyl-acrylate or methacrylate, acrylamide or methacrylamide, or a lower alkyl acrylate or methacrylate; if desired there may also be present in the monomer mixture (e) other polymerizable ethylenically unsaturated monomers, which are copolymerizable with components (a), (b), (c) and (d). The thus obtained anionic hydrogels are useful for combining by reaction or complexing, with water soluble or dispersible materials having an opposite charge; such as basic or cationic agricultural chemicals (insecticides, herbicides, fungicides, plant growth regulators, etc.), germicides, pharmaceuticals, cosmetics, hormones, enzymes, flavors, fragrances, antiperspirants, metals and the like, both to recover such basic or cationic materials from an aqueous medium and for purifying water containing them, and also for the preparation of a complex or other combination of the anionic hydrogel with such materials which may be useful per se or from which the complexed or combined basic or cationic material may be slowly or controllably released.
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RELATED APPLICATION
This application is a continuation-in-part of copending U.S. patent application Ser. No. 07/084,786, filed Aug. 13, 1987.
FIELD OF THE INVENTION
Herbicide antidotes are well-known crop protection chemicals. Of particular interest herein is a class of certain 5-heterocyclic-substituted oxazolidine and thiazolidine dihaloacetamide compounds found effective as antidotes for protecting crop plants from herbicide injury.
BACKGROUND OF THE INVENTION
Many herbicides injure crop plants at herbicide application rates necessary to control weed growth. Accordingly, many herbicides cannot be used for controlling weeds in the presence of certain crops. Uncontrolled weed growth, however, results in lower crop yield and reduced crop quality inasmuch as weeds compete with crops for light, water and soil nutrients. Reduction of herbicidal injury to crops without an unacceptable corresponding reduction of herbicidal action on the weeds can be accomplished by use of crop protectants known as herbicide "antidotes" or "safeners".
There are described in the literature various dihaloacyl oxazolidinyl and thiazolidinyl compounds containing a variety of substitutions on the oxazolidinyl or thiazolidinyl moiety, which compounds are known as antidotes, or safeners, for various herbicidal compounds in various crops. For example, a number of patents describe such dihaloacyl oxazolidinyl compounds having as substituents on the oxazolidinyl ring hydrogen, alkyl, cycloalkyl, spirocycloalkyl, alkoxyalkyl, alkanol, heterocycyl, aryl or aryloxyalkyl moieties, which compounds are used as antidotes for herbicides such as α-haloacetanilides or thiocarbamates in various crops. Typical of such patents are U.S. Pat. Nos. 3,959,304, 3,989,503, 4,072,688, 4,137,070, 4,124,372, 4,186,130, 4,197,110, 4,249,932, 4,256,481, 4,618,361 and 4,708,735 and EP Nos. 0054278, 0,147,365, 190,105 and 0,234,036.
None of the above patents or any other known to the inventors herein disclose any dihaloacyl oxazolidinyl or thiazolidinyl compounds directly substituted with a heterocyclic radical in the 5-position. The above EP 190,105 disclosed one dichloroacetyl oxazolidine compound having a furyl radical in the 2-position; that compound is not within the generic scope of the defined dichloroacetyl oxazolidine antidotes in that patent. The EP 0,234,036 discloses a great variety of dichloroacetic acid amide derivatives including various heterocyclic radicals such as 1, 3-oxazolidines which may be further substituted in non-designated positions with any of a plurality of radicals including the pyridyl and piperidinyl radicals, but the patent fails to exemplify any such compounds.
An effective herbicide must provide a relatively high level of control of grassy or broad-leaf weeds, or both, in the presence of crops in addition to meeting several other criteria. For example, the herbicide should possess relatively high unit activity so that lower rates of herbicide application are feasible. Lower application rates are desirable in order to minimize exposure of the environment to the herbicide. At the same time, such herbicide must be selective in herbicidal effect so as not to injure the crops. Herbicidal selectivity can be enhanced by use of an appropriate antidote in combination with the herbicide. But identification of an antidote which safens a herbicide in crops is a highly complicated task. Whether a compound or class of compounds provides efficacious antidote or safening activity is not a theoretical determination but must be done empirically. Safening activity is determined empirically by observing the complex inter-action of several biological and chemical factors, namely: the type of herbicide compound; the type of weed to be controlled; the type of crop to be protected from weed competition and herbicidal injury; and the antidote compound itself. Moreover, the herbicide and antidote must each possess chemical and physical properties enabling preparation of a stable formulation which is environmentally safe and easy to apply to the field.
SUMMARY OF THE INVENTION
A novel family of compounds useful as antidotes against herbicide injury to crops is provided by 5-heterocyclic-substituted oxazolidine dihaloacetamide compounds embraced by the general formula: ##STR1## and agriculturally-acceptable salts thereof wherein R is haloalkyl;
R 1 is C 1-4 alkyl, haloalkyl or phenyl;
R 2 -R 5 are H or C 1-4 alkyl;
R 6 is a saturated or unsaturated C 5-10 heterocyclic radical containing 1 to 2 oxygen, nitrogen or sulfur atoms, optionally substituted with a C 1-4 alkyl or haloalkyl radical or halogen atom or with oxygen on a ring nitrogen atom; and
R 5 and R 6 may be combined to form a spiroheterocyclic ring as defined for the R 6 radical.
The term "haloalkyl" embraces radicals wherein any one or more of the carbon atoms, preferably from 1 to 4 in number, is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically embraced by the term "haloalkyl" are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have either a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyl and polyhaloaklyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups. A dihaloalkyl group, for example, may have two bromo atoms, such as a dibromomethyl group, or two chloro atoms, such as a dichloromethyl group, or one bromo atom and one chloro atom, such as a bromochloromethyl group. Examples of a polyhaloalkyl are perhaloalkyl groups such as trifluoromethyl and perflouroethyl groups.
Preferred haloalkyl R members are dihalomethyl, particularly dichloromethyl, while the preferred haloalkyl R 1 member is a tri-halogenated methyl radical, preferably trifluoromethyl.
Where the term "alkyl" is used either along or in compound form (as in "haloalkyl"), it is intended to embrace linear or branched radicals having up to four carbon atoms, the preferred members being methyl and ethyl.
Also included in this invention are the stereo and optical isomers of compounds within the class defined by the above formula.
The heterocyclic R 6 member, alone or combined with the R 5 member to form a spiroheterocyclic radical through the 5-position carbon atom of the oxazolidinyl radical, can be saturated or unsaturated and contains five to ten ring members of which at least one member is a heterocyclic oxygen, nitrogen or sulfur atom. The heterocyclic ring may contain as many as four hetero atoms which may be the same or mixtures of said hetero atoms. The heterocyclic members of preference are the furanyl, thienyl and pyridinyl radicals. The heterocyclic ring may be substituted with one or more C 1-4 alkyl or haloalkyl radicals or with a halogen, preferably chloro, atom and with oxygen on a nitrogen hetero atom. As an R 6 member per se the heterocyclic ring must be attached directly to the 5-position of the oxazolidinone ring without any intervening moieties therebetween, e.g., an alkylene group.
It is further within the purview of this invention that in alternative embodiments, the oxazolidinyl radical may be substituted with a heterocyclic or spiroheterocyclic ring at the 2- and/or 4- carbon atoms, as described above for such substitutions on the 5- position carbon atom.
By "agriculturally-acceptable salts" of the compounds defined by the above formula is meant a salt or salts which readily ionize in aqueous media to form a cation of said compounds and a salt anion, which salts have no deleterious effect on the antidotal properties of said compounds or of the herbicidal properties of a given herbicide and which permit formulation of the herbicide-antidote composition without undue problems of mixing, suspension, stability, applicator equipment use, packaging, etc.
By "antidotally-effective" is meant the amount of antidote required to reduce the phytotoxicity level or effect of a herbicide, preferably by at least 10% or 15%, but naturally the greater the reduction in herbicidal injury the better.
By "herbicidally-effective" is meant the amount of herbicide required to effect a meaningful injury or destruction to a significant portion of affected undesirable plants or weeds. Although of no hard and fast rule, it is desirable from a commercial viewpoint that 80-85% or more of the weeds be destroyed, although commercially significant suppression of weed growth can occur at much lower levels, particularly with some very noxious, herbicide-resistant plants.
The preferred species of antidotal compounds according to this invention are
oxazolidine, 3-(dichloroacetyl)-5-(2-thienyl)-2,2-dimethyl-.
oxazolidine, 3-(dichloroacetyl)-5-(2-furanyl)-2,2-dimethyl-, and
oxazolidine, 3-(dichloroacetyl)-5-(3-pyridyl)-2,2-dimethyl-.
The terms "antidote", "safening agent", "safener", "antagonistic agent", "interferant", "crop protectant" and "crop protective", are often-used terms denoting a compound capable of reducing the phytotoxicity of a herbicide to a crop plant or crop seed. The terms "crop protectant" and "crop protective" are sometimes used to denote a composition containing as the active ingredients, a herbicide-antidote combination which provides protection from competitive weed growth by reducing herbicidal injury to a valuable crop plant while at the same time controlling or suppressing weed growth occurring in the presence of the crop plant. Antidotes protect crop plants by interfering with the herbicidal action of a herbicide on the crop plants so as to render the herbicide selective to weed plants emerging or growing in the presence of crop plants.
As further detailed infra, while not necessary, the composition containing the herbicide-antidote combination may also contain other additaments, e.g., biocides such as insecticides, fungicides, nematocides, miticides, etc., fertilizers, inert formulation aids, e.g., surfactants, emulsifiers, defoamers, dyes, etc.
Herbicides which may be used with benefit in combination with an antidote of the described class include preferably thiocarbamates (including dithiocarbamates), acetamides, heterocyclyl phenyl ethers (especially phenoxypyrazoles), imidazolinones, pyridines, and sulfonylureas. It is within the purview of this invention that the novel class of antidotal compounds be used with other classes of herbicides, e.g., triazines, ureas, diphenyl ethers, nitroanilines, thiazoles, isoxazoles, etc., the individual members of which classes may be derivatives having one or more substituents selected from a wide variety of radicals. Such combinations can be used to obtain selective weed control with low crop injury in several varieties of monocotyledonous crop plants such as corn, grain sorghum (milo), and cereals such as wheat, rice, barley, oats, and rye, as well as several varieties of dicotyledonous crop plants including oil-seed crops such as soybeans and cotton. Particular utility for the antidotal compounds of this invention has been experienced with various herbicides in corn, sorghum and soybeans.
Examples of important thiocarbamate herbicides are the following:
cis-/trans-2,3-dichloroallyl-diisopropyl-thiolcarbamate (common name "diallate");
ethyl dipropylthiocarbamate (common name "EPTC");
S-ethyl diisobutyl (thiocarbamate) (common name "butylate");
S-propyl dipropyl (thiocarbamate) (common name "vernolate");
2,3,3-trichloroallyl-diisopropylthiolcarbamate (common name "triallate")'
Examples of important acetamide herbicides are the following:
2-chloro-N-isopropylacetanilide (common name "propachlor");
2-chloro-1',6'-diethyl-N-(methoxymethyl)-acetanilide (common name "alachlor");
2-chloro-2',6'-diethyl-N-(butoxymethyl)-acetanilide (common name "butachlor");
2-chloro-N-(ethoxymethyl)-6'-ethyl-o-acetololuidide (common name "acetochlor");
ethyl ester of N-chloroacetyl-N-(2,6-diethylphenyl)glycine (common name "diethatyl ethyl");
2-chloro-N-(2,6-dimethylphenyl)-N-(2-methoxyethyl)acetamide (common name "metolachlor");
2-chloro-N-(2-methoxy-1-methylethyl)-6'-ethyl-o-acetotoluidide (common name "metolachlor");
2-chloro-2'-methyl-6'-methoxy-N-(isopropoxymethyl)acetanilide;
2-chloro-2',6'-dimethyl-N-(1-pyrazol-1-yl-methyl)acetanilide common name "metazachlor");
2-chloro-N(2,6-dimethyl-1chclohexen-1-yl)-N-(1H-pyrazol-1-ylmethyl)acetamide;
2-chloro-6'-trifluoromethyl-N-(isopropoxymethyl)acetanilide;
2-chloro-2'-methyl-6'-trifluoromethyl-N-(ethoxymethyl)acetanilide;
2-chloro-2'-ethyl-6'-trifluoromethyl-N-(1-pyrazolyl-1-ylmethyl)acetanilide;
2-chloro-N-isopropyl-1-(3,5,5-trimethylcyclohexen-1-yl)acetamide (common name "trimexachlor").
Examples of important pyridine herbicides include:
3-pyridinecarboxylic acid, 2-(difluoromethyl)-5-(4,5-dihydro-2-thiazolyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-, methyl ester;
3-pyridinecarboxylic acid, 2-(difluoromethyl)-4-(2-methylpropyl)-5-(1H-pyrazol-1-ylcarbonyl)-6-(trifluoromethyl)-, methyl ester;
3,5-pyridine dicarbothioic acid, 2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-, S,S-dimethyl ester;
3,5-pyridine dicarbothioic acid, 2-(difluoromethyl)-4-(2-methylpropyl)-6-trifluoromethyl, dimethyl ester.
Examples of important heterocyclyl phenyl ethers include:
5-(trifluoromethyl)-4-chloro-3-(3'[1-ethoxycarbonyl]-ethoxy-4'-nitrophenoxy)-1-methylpyrazol;
5-(trifluoromethyl)-4-chloro-3-(3'-[ethoxy-4'-nitrophenoxy)-1-methylpyrazole;
5-(trifluoromethyl)-4-chloro-3(3'-[1-butoxycarbonyl]-ethoxy-4'-nitrophenoxy)-4-methylpyrazol;
5-(trifluoromethyl)-4-chloro-3(3'-methylsulfanoylcarbonyl propoxy-1'-nitrophenoxy)-4-methylpyrazol;
5-(trifluoromethyl)-4-chloro-3-(3'-propoxycarbonylmethyloxime-4'-nitrophenoxy)-1-methylpyrazole;
(±)-2-[4-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenoxy]propanoic acid (9CI).
Examples of important sulfoylureas include:
Benzenesulfonamide, 2-chloro-N-[[)4-methoxy-6-methyl-1, 3, 5-triazin-2-yl) amino]carbonyl];
Benzoic acid, 2-[[[[(4-chloro-6-methoxy-2-pyrimidinyl) amino]carbonyl]amino]sulfonyl]-ethyl ester;
2-thiophenecarboxylic acid, 3-[[[[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-, methyl ester;
Benzoic acid, 2-[[[[(4, 6-dimethyl-2-pyrimidinyl) amino]carbonyl]amino]sulfonyl]methyl ester;
Benzenesulfonamide, 2-(2-chloroethoxy)-N-[[(4-methoxy-6-methyl-1, 3, 5-triazin-2-yl) amino]carbonyl];
Benzoic acid, 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-methyl ester;
Examples of important imidazolinone herbicides include:
3-Quinolinecarboxylic acid, 2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-;
3-pyridinecarboxylic acid, 2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2yl]-;
Benzoic Acid, 2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-4(or 5)-methyl-;
3-pyridinecarboxylic acid, 5-ethyl-2-[4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl];
3-pyridinecarboxylic acid, 2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-5-methyl-, ammonium salt.
Examples of other important herbicides include:
2-Chloro-4-(ethylamino)-6-(isopropylaminio)-sym-triazine;
4-Amino-6-terbutyl-3-(methylthio)-AS-triazine-5-(4H)one;
Trifluoro-2,6-dinitro-N,N-dipropyl-p-toluidine;
Benzeneamine, N-(1-ethylpropyl)-3, 4-dimethyl-2,6-dinitro-;
2-Pyrrolidinone, 3-chloro-4-(chloromethyl)-1-[3-(trifluoromethyl) phenyl], trans-;
3-Isoxazolidinone, 2-[(2-chlorophenyl) methyl]-4, 4-dimethyl-;
2-Imidazolidinone, 3-[5-(1,1-dimethylethyl)-3-isoxazolyl]-4-hydroxy-1-methyl-;
2-Chloro-4-(1-cyano-1-methylethylamino)-6-ethylamino-1,3,5-triazine;
2-Methoxy-3, 6-dichlorobenzoic acid, dimethylamine salt;
Methyl 5-(2,4-dichlorophenoxy)-2-nitrobenzoate;
1'-(Carboethoxy)ethyl 5-[2-chloro-4-(trifluoromethyl) phenoxy]-2-nitrobenzoate;
Ammonium-DL-homoalanin-4-yl (methyl) phosphinate;
2-(3,4-Dichlorophenyl)-4-methyl-1,2,4-oxadiazolidine-3,5-dione.
The herbicides of particular and preferred interest in compositions with antidotes according to this invention include each of the above-mentioned species from different chemical classes of compounds exemplified as important herbicides, particularly those of current commercial interest and use and those which may be determined of commercial utility.
alachlor,
acetochlor,
butachlor,
metolachlor,
metazochlor,
2-chloro-2'-methyl-6'-methoxy-N-(isopropoxymethyl)acetanilide,
2-chloro-2'-methyl-6'-trifluoromethyl-N-(ethoxymethyl)acetanilide, and
2-chloro-2',6'-dimethyl-N-(2-methoxyethyl)-acetanilide.
All of the above specifically-named herbicides are known in the art, except the heterocyclyl phenyl ethers which are disclosed and claimed in copending U.S. patent application Ser. No. 07/175,460 assigned to the assignee herein.
Combinations may be made of any one or more of the described antidote compounds with any one or more of the herbicide compounds mentioned herein.
Of particular importance and preference herein, a number of the antidotal compounds of the invention have been found to be especially versatile as "in-can" safeners or antidotes for use with a plurality of herbicides in a plurality of crops. Of special mention here is the use of the antidotes, oxazolidine, 3-(dichloroacetyl)-5-(2-furanyl)-2,2-dimethyl-; oxazolidine, 3-(dichloroacetyl)-5-(3-pyridyl)-2,2--dimethyl- and oxazolidine, 3-(dichloroacetyl)-5-(2-thienyl)-2,2-dimethyl-, to reduce the phytotoxicity of alachlor (active ingredient in LASSO® herbicide) in corn and grain sorghum. The just-named antidotes have similarly been found to be particularly efficacious against acetochlor (active ingredient in HARNESS® herbicide) in corn, sorghum and soybeans. And some of these antidotes, particularly the 5-(2-thienyl)oxazolidine compound, have also exhibited antidotal properties against butachlor (active ingredient in MACHETE® herbicide) in rice, particularly at higher rates, e.g., 8.96 kg/ha.
It will be recognized by those skilled in the art that all herbicides have varying degrees of phytotoxicity to various plants because of the sensitivity of the plant to the herbicide. Thus, e.g., although certain crops such as corn and soybeans have a high level of tolerance (i.e., low sensitivity) to the phytotoxic effect of alachlor, other crops, e.g., milo (grain sorghum), rice and wheat, have a low level of tolerance (i.e., high sensitivity) to the phytotoxic effects of alachlor. The same type of sensitivity to herbicides as shown by crop plants is also exhibited by weeds, some of which are very sensitive, others very resistant to the phytotoxic effects of the herbicide.
When the sensitivity of a crop plant to a herbicide is low, whereas the sensitivity of a weed to that herbicide is high, the "selectivity factor" of the herbicide for preferentially injuring the weed while not injuring the crop is high.
In an analogous manner, but more complex, an antidotal compound may, and commonly does, have varying degrees of crop protective effect against different herbicides in different crops. Accordingly, as will be appreciated by those skilled in the art, the various antidotes of this invention, as with all classes of antidotal compounds, will have greater or lesser crop safening effects against various herbicides in various crops than in others. Thus, while a given antidotal compound may have no crop protective ability against a given herbicide in a given crop, that same antidotal compound may have a very high crop protective ability against the same given herbicide in a different crop or against a different herbicide in the same crop. This is an expected phenomenon.
DETAILED DESCRIPTION OF THE INVENTION
Antidote Compound Preparation
The antidote compounds of the invention may be prepared by the following exemplary general procedures described in Examples 1-38.
These examples are presented for purposes of illustration only and are not intended as a restriction on the scope of the invention. All parts are by weight unless otherwise indicated.
Table I sets forth analytical data for 38 specific compounds prepared in accordance with these procedures.
EXAMPLE 1
Preparation of 3-(Dichloroacetyl)-2,2-Dimethyl-5-(2-Thienyl)-Oxazolidine
2-Thiophenecarboxaldehyde (28.3 g, 0.252 mol) was added to a mixture of cyanotrimethylsilane (25 g, 0.252 mol) and zinc iodide (1 mg), and the mixture was stirred at room temperature under nitrogen for 2 hours. The resulting silylcyanohydrin was distilled directly from the pot (BP 95° [email protected] torr) yielding 50.9 g (96%) of a pale yellow oil.
The silylcyanohydrin (0.241 mol) was taken up in 100 mL of anhydrous ether and was added dropwise to 13.7 g (0.361 mol) of lithium aluminum hydride in 400 mL of anhydrous ether under nitrogen cooled in an ice bath. The green colored reaction was stirred overnight then cooled in an ice bath, and was carefully quenched with 20 mL of water followed by 20 mL of 10% NaOH. After stirring for 30 min. anhydrous sodium sulfate was added and the mixture was filtered through celite. The filter cake was rinsed with THF and the filtrate was concentrated to give a solid which was recrystallized from methlene chloride--ether to give 25 g (72%) of α-(aminomethyl)-2-thiophenemethanol; MP 80°-82° C.
Twelve grams (12.0 g, 83.8 mmol) of the product in the preceding paragraph and acetone (9.7 g, 0.168 mol) in 85 mL of 1,2-dichloroethane were refluxed for 2 hours using a reverse water separator. Resulting mixture was concentrated giving an oil which was distilled to give 12.33 g (80%) of 2,2-dimethyl-5-(2-thienyl)oxazolidine, as a pale yellow oil (BP 102°-105° C. @1.5 torr).
To a stirred mixture of 4.0 g (21.83 mmol) of the product of the preceding paragraph in a biphasic mixture of 40 mL of methylene chloride (CH 2 Cl 2 ) and 20 mL of 10% NaOH cooled in an ice bath was added 2.5 mL (26.19 mmol) of dichloroacetyl chloride dropwise. The mixture was stirred for 20 min. and the layers separated. The aqueous layer was extracted with CH 2 Cl 2 and the combined organic layers dried over anhydrous magnesium sulfate (MgSO 4 ). The product was purified by chromatography on silica gel (Waters Prep. 500A, 10% ethylacetate-hexanes) and recrystallization from methylcyclohexane to give 3.87 g (60%) of the title compound. MP 104°-105° C.
EXAMPLES 2-5
Following substantially the same procedure described in Example 1, but substituting the appropriate heterocyclic aldehyde, the antidotal compounds of Examples 2-5 were prepared. These compounds are identified by structure and physical properties in Table 1 herein.
EXAMPLE 6
Example 6 is prepared using the same basic procedure as Example 1 with the following modifications. The starting material for Example 1, 2-thiophenecarboxaldehyde, is replaced by 3-furaldehyde. In addition, a benzene reflux is used to azeotrope water rather than 1,2-dichloroethane when forming the oxazolidine ring with acetone. The dichloroacetylation step is effected by placing 11.2 grams (0.067 mol) 2,2-dimethyl-5-(3-furan)-oxazolidine in methylene chloride at 0° C. with 9.5 g (0.094 mol) triethylamine and adding dropwise 11.8 grams (0.08 mol) dichloroacetyl chloride. The reaction mixture is washed with water and the organics dried with MgSO 4 . Concentration and chromatography with 10% ethylacetate-hexanes gives 5.1 grams (65%) of white solid; m.p. 90°-91° C.
EXAMPLES 7-12
Following the same procedure described in Example 6, but substituting the appropriate heterocyclic aldehyde, the antidotal compounds of Examples 7-12 were prepared. These compounds are described by structure and physical properties in Table 1 herein.
EXAMPLE 13
Following the procedure described in Example 1, but substituting diethyl ketone for aceton, the compound identified as Example 13 in Table 1 was prepared and characterized.
EXAMPLES 14 and 15
The compounds of Examples 14 and 15 in Table 1 were prepared in accordance with the basic procedure of Example 1 above, substituting 2-furaldehyde and 3-methyl-2-thiophenecarboxaldehyde, respectively, for 2-thiophenecarboxaldehyde and acetaldehyde for acetone, and with the following additional modification in Example 14. In Example 14 the oxazolidine ring is formed by placing 5.0 grams (0.04 mol) 1-furanmethanol alpha-(aminomethyl)-and 1.8 grams (0.04 mol) acetaldehyde in methylene chloride in the presence of MgSO 4 for 2 hours. After filtration and then cooling to 0°°C., 4.3 g (0.06 mol) pyridine was added. After the addition of 6.9 grams (0.05 mol) dichloroacetyl chloride the reaction mixture is washed with water and the organics are dried over MgSO 4 . Concentration and chromatography with 10% ethyl acetate-hexanes gives 2.0 grams (19%) of colorless oil.
EXAMPLE 16
Following substantially the same procedure as in Example 14, but substituting propionaldehyde instead of acetaldehyde, the product identified as Example 16 in Table 1 was produced.
EXAMPLE 17
In similar manner, when the procedure of Example 14 was repeated using benzaldehyde instead of acetaldehyde, there was obtained the product of Example 17 as identified in Table 1.
EXAMPLE 18 and 19
To prepare antidotal compounds according to the invention having mixed halogen atoms at the 3-haloacyl position, the procedure of Example 6 was repeated, but substituting bromochloroacetyl chloride as the acylating agent instead of dichloroacetyl chloride. In this manner, the compounds identified in Table 1 as Examples 18 and 19 were prepared and characterized.
EXAMPLE 20
Pyridine, 3-[3-(dichloroacetyl)-2,2-dimethyl-5-oxa zolidinyl]-.
To a cooled stirring solution of 15 grams (0.25 mol) nitromethane and 0.35 gram (0.005 mol) diethylamine in 26 milliliters of ethanol was added dropwise 10 grams (0.093 mol) 3-pyridine carboxaldehyde. The reaction was stirred for 3 hours at 0° C. then warmed to ambient temperature. Concentration yielded crude 1-(3-pyridyl)-2-nitroethanol.
The above product was dissolved in ethyl alcohol and added to 8 grams of 10% palladium on carbon. The mixture was hydrogenated in a Parr Shaker at 45 psi until 3 mol equivalents of hydrogen were reacted. Filtration through celite and concentration yielded a crude 2-(3-pyridyl)-2-hydroxy-1-aminoethane.
The product of the preceding paragraph and 10.9 grams (0.19 mol) acetone were stirred in 150 milliliters benzene and refluxed for 4 hours in a Dean-Stark apparatus to remove water. The reaction mixture was decanted from any solid and concentrated to a crude pyridine, 3-(2,2-dimethyloxazolidinyl)-.
The oxazolidinyl compound of the preceding step and 10.3 grams (0.102 mol) triethylamine were stirred at 0° C. in CH 2 Cl 2 . 12.9 grams (0.088 mol) dichloroacetyl chloride were added dropwise and the reaction mixture was stirred for 30 minutes at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction was worked up by washing with water, separation and drying the organics with Na 2 SO 4 . Filtration and concentration yielded crude product which when chromatographed with 60% ethylacetate-hexanes gave 7% overall yield of the title compound (1.8 grams, cream colored solid, M.P. 111°-113° C.)
The product of this example can also be prepared according to the procedure of Example 1.
EXAMPLE 21
Three (3) grams (0.01 mol) of the product of Example 20 and 1.1 gram (0.013 mol) of NaHCO 3 were stirred in CH 2 Cl 2 . To this mixture was added 2.15 grams (0.01 mol) of m-chloroperbenzoic acid in two portions and stirred for one hour. The reaction mixture was washed with water and dried with MgSO 4 . The MgSO 4 was filtered and the CH 2 Cl 2 was removed to yield a white solid. Flash chromatography using 20% methanol, 30% ethylacetate 50% hexanes was done on the crude product. After concentration and placing under high vacuum for 24 hours at room temperature an amorphous solid was collected. (MP=64°-70° C., 2.5 grams, 82% yield). The product was identified as pyridineoxide, 2-[3-(dichloroacetyl)2,2-dimethyl-5-oxazolidinyl]-.
EXAMPLE 22
Two (2) grams (0.007 mol) of the product of Example 20 were dissolved in CH 2 Cl 2 and 1.2 gram (0.007 mol) of methyl trifluoromethyl sulfonate was added dropwise. A colorless solid precipitated after 30 minutes which was filtered and collected under nitrogen. 2.7 grams (86% yield) of product was collected (M.P. 151°-153° C.) and identified as pyridinium, 3-[3-(dichloroacetyl)-2,2-dimethyl-5-oxazolidinyl]-1-methyl-, salt of trifluoromethane sulfonic acid (1:1).
EXAMPLE 23
Caution: This procedure uses HCN which is highly toxic and requires special handling.
19.2 grams (0.2 mol) of freshly distilled 2-furaldehyde and 40 milligrams of mandelonitrile lyase (4.1.2.10) were dissolved in 480 milliliters of 50% methanol-acetate buffer (pH=5.2) 7.1 grams (0.26 mol) of HCN were added over 10 minutes with vigorous stirring to this reaction mixture. The reaction mixture was stirred for 40 minutes at room temperature and then placed under vacuum for 15 minutes to remove excess HCN. Extraction was effected using CHCl 3 (3×150 mls) and then the organics were dried using MgSO 4 . After filtration and concentration, 21 grams of 83% enantiomerically pure oil, 2-(1-hydroxy-2-cyanoethyl)-furan (S) was collected. Optical rotation [α] D 21 =+28.5° (C=5, chloroform; Lit value [α] D 20 =+30.6° C. neat)
Seven (7.0) grams (0.057 mol) of the above product were dissolved in anhydrous ethyl ether and added dropwise to 74 milliliters of 1 M ethyl ether solution of lithium aluminum hydride (LAH) under nitrogen. The reaction mixture was stirred 5 hours and then the excess LAH was destroyed by adding dropwise 5 milliliters of H 2 O and 5 milliliters of 10% NaOH (aq). The mixture was filtered and concentrated to give 4 grams of colorless solid (55% yield). Recrystallization from ethyl acetate--hexane yielded 2-(1-hydroxy-2-aminoethyl)-furan (S) with a melting point equal to 74°-77° C. Optical rotation [α] D 21 =-23.6° (C=5, chloroform; Lit value [α] D 21 =-28° C=5, chloroform)
Two (2.0) grams (0.016 mol) of the product of the preceding paragraph, 1.8 grams (0.031 mol) of acetone and 50 milliliters of benzene were stirred together at reflux for 40 hours in a dean Stark apparatus. After 0.2 milliliters of H 2 O was removed, the reaction was cooled and concentrated to collect 2.58 grams (96% yield) of amber oil, 2,2-dimethyl-5-(2-furyl)oxazolidine (S).
2.58 grams (0.015 mol) of the above oxazolidine compound was dissolved in CH 2 Cl 2 and cooled to 0° C. at which time 2.18 grams (0.02 mol) of triethylamine was added in one portion with stirring. Dropwise addition of 2.17 grams (0.019 mol) of dichloroacetyl chloride was effected and the reaction was stirred for an additional 30 minutes at 0° C. The reaction was warmed to room temperature, washed with water and the organics were dried with Na 2 SO 4 . Filtration and concentration yielded 5.0 grams of dark oil which was chromatographed using 10% ethyl acetate-hexane. 2.5 grams of colorless product were collected and identified as oxazolidine, 3-(dichloroacetyl)-5-(2-furanyl)-2,2-dimethyl-, (S); (m.p.=116°-119° C., yield=60%). Optical rotation [α] D 21 =+10.8° (C=5, chloroform).
EXAMPLE 24
Six grams (0.05 mol) of 2-(1-hydroxy-1-aminoethyl)-furan, 2.8 grams (0.05 mol) acetic acid and 10.6 grams (0.1 mol) 1,1,1-trifluoromethyl acetone were refluxed in benzene for 1.5 hours while removing water via a Dean-Stark apparatus. The reaction mixture was concentrated and the acetic acid was removed on a Kugelrohr without heating, and then the product was distilled over at 80°-100° C. (high vacuum). 8.4 grams of colorless oil was collected (76% yield) and identified as oxazolidine, 5-(2-furanyl)-2-methyl-2-trifluoromethyl-.
One (1.0) gram (0.005 mol) of the above oxazolidine and 0.7 gram (0.005 mol) dichloroacetyl chloride were refluxed in toluene for 4 hours. The reaction mixture was concentrated and flash chromatography was run with 5% ethyl acetate-hexanes on the crude product. Three-fourth (0.75) gram (45% yield) of white solid, was collected and identified as oxazolidine, 3-(dichloroacetyl)-2-methyl-5-(2-furanyl)-2-(trifluoromethyl)-; m.p.=97°-100° C. as a mixture of diasteroisomers.
EXAMPLES 25 and 26
Following substantially the same procedure described in Example 24, but substituting 2-(1-hydroxy-1-aminoethyl)-thiophene for the -furanyl analog, 3.3 g (5.6% yield) of white solid was separated and identified as an isomeric mixture of cis- and trans- oxazolidine, 3(dichloroacetyl)-2-methy-5-(2-thienyl)-2-(trifluoromethyl)-. The diastereoisomers were separated by chromatography using 10% ethylacetate and hexanes. The isomeric compounds were recovered in a ratio of 2:1 (trans-:cis-). MP of the trans-isomer, 89°-90° C. and of the cis-isomer, 96°-97° C. The structures of these isomers were tentatively assigned by NMR and molecular modeling.
EXAMPLE 27
This example describes the preparation of an antidotal compound according to the invention wherein the R 5 and R 6 members of the above generic formula are combined with the 5-carbon atom of the oxazolidine ring to form a six-membered spiroheterocyclic radical.
The process of Example 6 was repeated, except the 3-furaldehyde of that example was replaced by tetrahydrothiopyran-4-one as the starting heterocyclic radical donor. After reaction and workup as described in Example 6, there was recovered 4.5 g 56% yield) of a white-colored solid MP 137°-139° C., which was identified as 1-oxa-8-thia-3-azaspiro [4.5]-decane, 3-(dichloroacetyl)-2,2-dimethyl-.
EXAMPLE 28
This example describes the preparation of an antidotal compound wherein the R 5 and R 6 members of the above generic formula are combined with the 5-carbon atom of the oxazolidinyl ring to form a 5-membered spiroheterocyclic radical.
The process according to Example 6 was repeated, except the 3-furaldehyde of that example was replaced by tetrahydrothiophene-3-one as the heterocyclic radical donor starting material. After reaction and workup as described in Example 6, 5.5 g (65% yield) of a white-colored solid MP 128°-130° C., was recovered. The compound was identified as 1-oxa-7-thia-3-azaspiro [4.4]-nonane, 3-(dichloroacetyl)-2,2-dimethyl-.
EXAMPLE 29
The process of Example 14 was repeated, except in this example, the starting material of Example 14 was replaced by tetrahydrothiopyran-4-one. After reaction and workup, 5.0 g (65% yield) of a white-colored solid, MP 109°-111° C. was recovered. The compound was identified as 1-oxa-8-thia-3-azaspiro [4.5]-decane, 3-(dichloroacetyl)-2-methyl-.
EXAMPLE 30
The process of Example 14 was followed, except the starting material of Example 14 was replaced by tetrahydrothiophene and the acetaldehyde was replaced by propionaldehyde. After workup, 5.8 g (53% yield) of a colorless oil was recovered. The compound was identified as 1-oxa-7-thia-3-azaspiro [4.4]-nonane, 3-(dichloroacetyl)-2-ethyl-.
EXAMPLE 31
This example describes the preparation of an antidotal compound according to the invention, characterized by an alkyl substitution in the 4-position and by a 5-furanyl substitution.
The process of Example 20 was again repeated, except in this process 2-furaldehyde was used in place of the 3-pyridinecarboxaldehyde of Example 20 and nitroethane was used instead of nitromethane in the first step of the action.
After workup, 0.4 g (3% yield) of a white-colored solid, MP 128°-131° C. was recovered. The compound was identified as oxazolidine, 3-(3-dichloroacetyl)-5-(2-furanyl)-2,2,4-trimethyl-.
EXAMPLE 32
Another antidotal compound exemplary of those of this invention is characterized by substitution of a pyrazinyl radical in the 5-position of the oxazolidine ring.
The process of this example followed that of Example 20, but for the substitution of 2-pyrazinecarboxaldehyde for the 3-pyridinecarboxaldehyde of Example 20.
After reaction and workup, 0.9 g (5% yield) of a tan-colored solid, MP 94°-96° C. was recovered. The product was identified as pyrazine, 3-[3-(dichloroacetyl)-2,2-dimethyl-5-oxazolidinyl].
EXAMPLE 33
To a solution of 9.2 mL (0.105 mol) of oxalyl chloride in 200 mL of anhydrous methylene chloride under nitrogen at -78° C. was added 7.8 mL (0.11 mol) of anhydrous dimethylsulfoxide dropwise over several minutes. Following the addition the mixture was allowed to warm to -35° C. and after five minutes was recooled to -78° C. A solution of 10.2 g (0.10 mol) of tetrahydrofurfural alcohol in 100 mL of anhydrous methylene chloride was added. The reaction was warmed to -35° C. then 70 mL (0.50 mol) of triethylamine was added over a five minute period. The reaction was recooled to -78° C. and was stirred at that temperature for two hours. The mixture was then filtered followed by washing the filtrate with 350 mL of 5% hydrochloric acid. The aqueous layers were backwashed with two portions of methylene chloride. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated (>10° C., 100 torr) to ca. 20 mL volume to give a mixture of the desired aldehyde and methylene chloride. This mixture is treated with 13.3 mL (0.10 mol) of trimethylsilylcyanide and 10 mg of zinc iodide. The mildly exothermic reaction is stirred under nitrogen at room temperature for one hour followed by concentration in vacuo. The resulting oily silyl cyanohydrin was taken up in 150 mL of anhydrous ether. Cooled mixture in an ice bath under nitrogen followed by the addition of 100 mL of a 1 M lithium aluminum hydride solution in ether. The reaction is mechanically stirred at room temperature for two hours and is then recooled with an ice bath followed by the cautious dropwise addition of 3 mL of water then 6 mL of a 10% sodium hydroxide solution. Diluted mixture with 200 mL of tetrahydrofuran and stirred at room temperature for 45 minutes. Anhydrous sodium sulfate was added to absorb excess water followed by filtration through celite and concentration in vacuo to give the amino alcohol as an amber oil. The amino alcohol was dissolved in 100 mL of acetone. About 5 g of anhydrous magnesium sulfate was added followed by stirring overnight at room temperature. Filtration and concentration in vacuo gave the oxazolidine as an amber oil. The oxazolidine was dissolved in 150 mL of methylene chloride followed by the addition of 75 mL of 10% sodium hydroxide. The mixture was cooled in an ice bath and was treated with 9.6 mL (0.10 mol) of dichloroacetyl chloride. The reaction was vigorously stirred for 45 minutes. The layers were then separated and the organic phase was dried over anhydrous magnesium sulfate. Thin layer chromatography (ethyl acetate:hexanes=1,1) and gas chromatography show the presence of the title product as a mixture of two diasteromers. The mixture was resolved by flash chromatography on silica gel (ethyl acetate:hexanes 1:4). The two diasteromers were isolated: (A) 3.46 g of the less polar isomer was isolated as a yellow oil n D 25 =1.4991. Anal. calc'd for C 11 H 17 Cl 2 NO 3 : C,46.82; H,6.07; Cl, 25.13. Found: C,46.52; H,6.01; Cl,25.01. (B) 2.00 g of the more polar isomer as a yellow oil n D 25 =1.5021. Anal. Calc'd for C 11 H 17 Cl 2 NO 3 : C,46.82; H,6.07; Cl25.13. Found: C,46.58; H,6.00; Cl,24.97. The overall yield for the fix steps is 19%. The product was identified as 3-(dichloroacetyl)-2,2-dimethyl-5-(tetrahydro-2-furanyl)-oxazolidine.
EXAMPLE 34
Using the same basic procedure described in Example 6, but substituting monochloroacetyl chloride in the last step, the compound oxazolidine, 3-(chloroacetyl)-5-(2-furanyl)-2, 2-dimethyl was prepared.
EXAMPLE 35
Following the procedure of Example 6, but substituting trichloroacetyl chloride in the last step of the reaction there was prepared oxazolidine, 5-(2-furanyl)-2,2-dimethyl-3-(trichloracetyl)-.
EXAMPLE 36
Using the same procedure as Example 6, but substituting 2-thiophene-methanol for tetrahydrofurfuralalcohol and using monofluoroacetyl chloride in the last step, the compound oxazolidine, 3-(fluoroacetyl) 2,2-dimethyl-5-(2-thienyl) was prepared. MP 65°-67° C.
EXAMPLE 37
The compound oxazolidine, 3-(dichloracetyl)-5-(2-thienyl- was prepared using the same basic procedure as Example 6 with the following modifications: the cyclization of the 2-thiophenemethanol, alpha-(aminomethyl)-, with formaldehyde to form the oxazolidine ring was effected by dissolving the 2-thiophenemethanol, alpha-(aminomethyl)-, in water and then adding the formaldehyde in one portion. The resulting oil that drops out is extracted with methylene chloride and dried with anhydrous magnesium sulfate (MgSO 4 ). Filtration and concentration gave a crude product which was acetylated with dichloroacetyl chloride to give the above compound.
EXAMPLE 38
The same basic procedure as in example 6 was repeated with the following modifications: the cyclization of the 2-benzofuranmethanol, alpha-(aminomethyl)-, with acetone was effected by stirring the two together at ambient temperature until a homogeneous solution resulted. After which the solution was dried with anhydrous magnesium sulfate (MgSO 4 ). Filtration and concentration gave a crude product that was acetylated to yield oxazolidine, 5-(2-benzofuranyl)-3-(dichloroacetyl)-2, 2-dimethyl- MP 115°-117° C.
Various other compounds with the above generic formula and analogs thereof are specifically contemplated as within the scope of the invention. For example, compounds according to the above formula where the oxygen atom of the oxazolidinyl radical is replaced by a sulfur atom (to form the thiazolidinyl analog) and the R-R 6 members are as defined above may be found to have varying degrees of antidotal activity against various herbicides in various crops. Particularly contemplated are such thiazolidinyl compounds wherein R is dichloromethyl, the R 1 -R 5 members hydrogen or C 14 alkyl and the R 6 member is a thienyl, furanyl, pyranyl, pyrazinyl or pyridinyl radical or the 5,5-spiro analogs thereof. Exemplary species include thiazolidine, 3-(dichloroacetyl)-5-(2-furanyl)-2,2-dimethyl-; thiazolidine, 3-(dichloroacetyl)-5-(2-thienyl)-2,2-dimethyl-; thiazolidine, 3-(dichloroacetyl-2,2-dimethyl 5-(1-methyl-1H-pyrrol-2-yl)-; thiazolidinyl, 3-(dichloroacetyl)-5-(3-pyridyl)-2,2-dimethyl- and thiazolidinyl, 3-(dichloroacetyl)-5-(2-pyrazyl)-2,2-dimethyl-. As with the oxazolidinyl analogs, the foregoing thiazolidinyl compounds and analogs thereof may be characterized as having H or other lower alkyl groups in the R 1 -R 5 positions.
The antidotal compounds prepared in accordance with the foregoing working examples are listed in Table 1. The specific compounds are listed in the first column by example/antidote number ("Ex./Antidote No.") followed by structural features according to the generic formula at the head of the table and by process yield and physical characteristics in the remaining columns.
TABLE 1 ##STR2## Anal. Ex./Antidote No. R R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6 Yield (Wt. %) MP (°C.) Elem. Cal'd. F'nd 1 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR3## 60 104-105 CHCl 44.91 4.4524.10 45.02 4.4924.04 2 CHCl.sub.2 CH.sub.3 C H.sub.3 H H H ##STR4## 26 91-93 CHCl 46.76 4.9123.00 46.85 4.9622.95 3 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR5## 50 95-96 CHCl 47.50 4.7125.49 47.64 4.7225.42 4 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR6## 47 94-96 CHCl 46.76 4.9123.00 46.81 4.9522.92 5 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR7## 47 84-87 CHCl 44.91 4.4524.10 44.98 4.4624.01 6 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR8## 65 90-91 C HCl 47.50 4.7125.49 46.42 4.6424.55 7 CHCl.sub.2 CH.sub.3 CH.sub.3 H H CH.sub.3 ##STR9## 77 82-84 CHN 46.76 4.91 4.54 46.82 5.02 4.46 8 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR10## 71 78-80 CHN 49.33 5.18 4.79 49.43 5.26 4.71 9 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR11## 53 100-102 CHN 52.50 5.32 9.24 51.55 5.35 9.20 10 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR12## 57 107-108 CHN 49.50 5.54 9.62 39.32 5.60 9.59 11 CHCl.sub.2 CH.sub.3 CH.sub.3 H H CH.sub.2 CH.sub.3 ##STR13## 9 65-68 CHN 48.45 5.32 4.35 48.53 5.38 4.31 12 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR14## 9 115-116 CHN 33.23 2.53 7.05 33.21 2.57 7.04 13 CHCl.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H H H ##STR15## 39 80-82 CHCl 48.45 5.3222.00 48.52 5.3521.92 14 CHCl.sub.2 CH.sub.3 H H H H ##STR16## 19 N.sub.D.sup.26 1.5300 CHN 45.48 4.20 5.30 45.10 4.29 5.20 15 CHCl.sub.2 CH.sub.3 H H H H ##STR17## 63 N.sub.D.sup.26 1.5530 CHN 44.91 4.45 4.76 45.18 4.51 4.84 16 CHCl.sub.2 C.sub.2 H.sub.5 H H H H ##STR18## 32 N.sub.D.sup.24 1.5160 CHN 47.50 4.71 5.04 47.41 4.69 4.87 17 CHCl.sub.2 φ H H H H ##STR19## 32 126-128.5 CHN 55.24 4.02 4.29 55.31 4.06 4.30 18 CHBrCl CH.sub.3 C H.sub.3 H H H ##STR20## 45 102-103 CHN 40.96 4.06 4.34 41.13 4.11 4.37 19 CHBrCl CH.sub.3 CH.sub.3 H H H ##STR21## 42 101-102.5 CHN 39.01 3.87 4.14 39.11 3.89 4.11 20 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR22## 11 111-112 CHN 49.84 4.88 9.69 49.92 4.90 9.68 21 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR23## 82 64-70 CHN 47.23 4.62 9.18 46.49 4.84 8.69 22 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR24## 86 151-153 CHN 37.10 3.78 6.18 37.19 3.82 6.14 23 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR25## 60 116-119 CHN 47.50 4.71 5.04 47.51 4.74 5.00 24 CHCl.sub.2 CF.sub.3 CH.sub.3 H H H ##STR26## 45 97-100 CHN 39.78 3.04 4.22 39.94 3.07 4.27 25 CHCl.sub.2 . . . CF.sub.3 CH.sub.3 H H H ##STR27## 37 89-90 CHN 37.95 2.90 4.02 38.01 2.91 4.02 26 CHCl.sub.2 CF.sub.3 . . . CH.sub.3 H H H ##STR28## 19 96-97 CHN 37.95 2.90 4.02 38.00 2.92 4.01 27 CHCl.sub.2 C H.sub.3 CH.sub.3 H H ##STR29## 56 137-139 CHN 44.30 5.75 4.70 44.48 5.73 4.69 28 CHCl.sub.2 CH.sub.3 CH.sub.3 H H ##STR30## 65 128-130 CHN 42.26 5.32 4.93 42.54 5.27 4.86 29 CHCl.sub.2 CH.sub.3 H H H ##STR31## 65 109- 111 CHN 42.26 5.32 4.93 42.55 5.47 4.91 30 CHCl.sub.2 C.sub.2 H.sub.5 H H H ##STR32## 53 N.sub.D.sup.26 1.5406 CHN 42.26 5.32 4.93 42.58 5.21 4.8231 CHCl.sub.2 CH.sub.3 CH.sub.3 H CH.sub.3 H ##STR33## 3 128-131 CHN 49.33 4.19 4.79 49.35 5.19 4.77 32 CHCl.sub.2 CH.sub.3 C H.sub.3 H H H ##STR34## 5 94-96 CHN 45.53 4.5314.49 44.95 4.4714.30 33(A) CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR35## Yellow OilN.sub.D.sup.25 1.4991 CHCl 46.82 6.0725.13 46.52 6.0125.01 19 33(B) CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR36## Yellow OilN.sub.D.sup.25 1.5021 CHCl 46.82 6.0725.12 46.58 6.0024.97 34 CH.sub.2 Cl CH.sub.3 CH.sub.3 H H H ##STR37## 73 67-69 CHN 54.22 5.79 5.75 54.10 5.85 5.69 35 CCl.sub.3 CH.sub.3 CH.sub.3 H H H ##STR38## 70 90-92 CHN 42.27 3.87 4.48 42.32 3.88 4.43 36 CH.sub.2 F CH.sub.3 CH.sub.3 H H H ##STR39## 88 65-67 CHN 54.30 5.80 5.76 54.16 5.83 5.74 37 CHCl.sub.2 H H H H H ##STR40## 8 N.sub.D.sup.20 1.5790 CHN 40.62 3.41 5.26 40.66 3.43 5.22 38 CHCl.sub.2 CH.sub.3 CH.sub.3 H H H ##STR41## 38 115-117 CHN 54.90 4.61 4.27 54.98 4.62 4.26
BIOLOGICAL EVALUATION
Effective weed control coupled with low crop injury is a result of treatment of a plant locus with a combination of herbicide compound and antidote compound. By application to the "plant locus" is meant application to the plant growing medium, such as soil, as well as to the seeds, emerging seedlings, roots, stems, leaves, or other plant parts.
The phrase "combination of herbicide compound and antidote compound" embraces various methods of treatment. For example, the soil of a plant locus may be treated with a "tank-mix" composition containing a mixture of the herbicide and the antidote which is "in combination". Or, the soil may be treated with the herbicide and antidote compounds separately so that the "combination" is made on, or in, the soil. After such treatments of the soil with a mixture of herbicide and antidote or by separate or sequential application of the herbicide and antidote to the soil, the herbicide and antidote may be mixed into or incorporated into the soil either by mechanical mixing of the soil with implements or by "watering in" by rainfall or irrigation. The soil of a plant locus may also be treated with antidote by application of the antidote in a dispersible-concentrate form such as a granule. The granule may be applied to a furrow which is prepared for receipt of the crop seed and the herbicide may be applied to the plant locus either before or after in-furrow placement of the antidote-containing granule so that the herbicide and antidote form a "combination". Crop seed may be treated or coated with the antidote compound either while the crop seed is in-furrow just after seeding or, more commonly, the crop seed may be treated or coated with antidote prior to seeding into a furrow. The herbicide may be applied to the soil plant locus before or after seeding and a "combination" is made when both herbicide and antidote-coated seed are in the soil. Also contemplated as a "combination" is a commercially-convenient association or presentation or presentation of herbicide and antidote. For example, the herbicide and antidote components in concentrated form may be contained in separate containers, but such container may be presented for sale or sold together as a "combination". Or, the herbicide and antidote components in concentrated form may be in a mixture in a single container as a "combination". Either such "combination" may be diluted or mixed with adjuvants suitable for soil applications. Another example of a commercially-presented combination is a container of antidote-coated crop seed sold, or presented for sale, along with a container of herbicide material. These containers may, or may not, be physically attached to each other, but nontheless constitute a "combination of herbicide and antidote" when intended for use ultimately in the same plant locus.
In the foregoing description of various modes of application of the herbicide-antidote combinations, it is inherent that each form of application requires that in some manner, the herbicide and antidote will physically combine to form a "composition" of those agents.
The amount of antidote employed in the methods and compositions of the invention will vary depending upon the particular herbicide with which the antidote is employed, the rate of application of the herbicide, the particular crop to be protected, and the manner of application to the plant locus. In each instance the amount of antidote employed is a safening-effective amount, that is, the amount which reduces, or protects against, crop injury that otherwise would result from the presence of the herbicide. The amount of antidote employed will be less than an amount that will substantially injure the crop plant.
The antidote can be applied to the crop plant locus in a mixture with the selected herbicide. For example, where the crop seed is first planted, a suitable mixture of antidote and herbicide, whether in a homogeneous liquid, emulsion, suspension or solid form, can be applied to the surface of, or incorporated in, the soil in which the seed has been planted. Or, the herbicide-antidote mixture may be applied to the soil, and the seed thereafter "drilled" into the soil below the soil layer containing the herbicide-antidote mixture. The herbicide will reduce or eliminate the presence of undesirable weed plants. Where the herbicide would by itself injure the crop seedlings, the presence of the antidote will reduce or eliminate the injury to the crop seed caused by the herbicide. It is not essential that the application of herbicide and the antidote to the plant locus be made using the selected herbicide and antidote in the form of a mixture or composition. The herbicide and the antidote may be applied to the plant locus in a sequential manner. For example, the antidote may be first applied tot he plant locus and thereafter the herbicide is applied. Or, the herbicide may be first applied to the plant locus and thereafter the herbicide is applied.
The ratio of herbicide to antidote may vary depending upon the crop to be protected, weed to be inhibited, herbicide used, etc., but normally a herbicide-to-antidote ratio ranging from 1:25-to-60:1 (preferably 1:5-to-30:1) parts by weight may be employed. As indicated above, the antidote may be applied to the plant locus in a mixture, i.e., a mixture of a herbicidally-effective amount of herbicide and a safening-effective amount of an antidote, or sequentially, i.e., the plant locus may be treated with an effective amount of the herbicide followed by a treatment with the antidote or vice versa. In general, effective herbicidal amounts are in the range of about 0.1 to about 12 kilograms/hectare. The preferred range of rate of application is from about 0.4 to about 10 kg/ha. Preferably, antidote application rates range from about 0.5 kg/ha down to about 0.05 kg/ha. It will be appreciated that at times amounts either below or above these ranges will be necessary to obtain the best results. The selection of the herbicide to inhibit the emergence and growth of weeds depends upon the species of weeds to be controlled and the crop to be protected.
The application of the antidote can be made directly to the seed before planting. In this practice, a quantity of crop seed is first coated with the antidote. The coated seed is thereafter planted. The herbicide may be applied to the soil before or after the coated seed is planted.
Evaluations of safening activity of the antidote compounds of this invention were carried out using the specific procedures of Examples 39-42 in greenhouse testing. Measurements of biological response as reported in Tables 2-5 were made in the following manner. A visual comparison was made between a crop plant treated with herbicide along and crop plant having no herbicide or antidote treatment. A number was assigned to this visual comparison indicating the percent injury or inhibition to the herbicide-alone treated crop plant (column "WO" in Tables 2-5 indicating herbicide "without" antidote). Also, a visual comparison was made between the crop plant treated with herbicide+antidote combination and the crop plant having no herbicide or antidote treatment. A number was assigned to this visual comparison indicating the percent injury or inhibition to the herbicide+antidote treated crop plant (column "W" in Tables 2-5 indicating herbicide "with" antidote). Where treatments involved weed plant species, observations of response to herbicide or herbicide+antidote were similarly recorded. The degree of reduction of herbicide injury provided by an antidote compound is indicated by the magnitude that the plant inhibition number of column "WO" exceeds the corresponding number of column "W". also reported in Tables 2-5 are data in parenthesis showing "safening effect" (defined below) for the herbicide+antidote combinations calculated from the plant inhibition numbers. These tables show crop or weed column headings under which there are no data. The lack of such data is not an indication of a failed test; rater it is merely an indication that the particular herbicide+antidote rate combination was not tested with that crop or weed. Summarized below is key information for interpreting data reported in Tables 2-5:
______________________________________HerbicideNo. Name______________________________________1. 2,3,3-trichloroallyl-N,N-diisopropyl- thiocarbamate(triallate)2. 2-chloro-2',6'-diethyl-N-(methoxymethyl)- acetanilide (alachlor)3. 2-chloro-2',6'-diethyl-N-(butoxymethyl)- acetanilide (butachlor)4. 2-chloro-2'-methyl-6'-methoxy-N-(iso- propoxymethyl)acetanilide5. 3,5-pyridinecarboxylic acid, 2-(difluoro- methyl)-4-(2-methylpropyl)-6-trifluoro- methyl, dimethyl ester6. ethyl dipropylthiocarbamate7. α,α,α-trifluoro-2,6-dinitro-N,N-dipropyl- -p-toluidine8. 2-chloro-N-(2-methoxyethyl)- -o, -o-aceto- xylidide9. 2-chloro-N-(2-methoxy-1-methylethyl)- 6'-ethyl- -o-acetotoluidide10. 2-chloro-2',6'-dimethyl-N-(1-pyrazol- 1-ylmethyl)acetanilide11. 2-chloro-2'-methyl-6'-trifluoromethyl-N- (ethoxymethyl)acetanilide12. 2-pyrrolidinone, 3-chloro-4-(chloro- methyl)-1-[3-(trifluoromethyl)phenyl]-, trans-13. 2-chloro-N-(ethoxymethyl)-6'-ethyl- -o- acetotoluide14. cis-trans-2,3-dichloroallyl N-benzyl- dithiocarbamate______________________________________ Antidote No. = Compound in corresponding Example No. Rate = kilograms/hectare (kg/ha). W = % Plant Inhibition caused by combination of herbicide and antidote. WO = % Plant Inhibition caused by herbicide alone. Data reported in parentheses = % Safening Effect ##STR42##
EXAMPLE 39
The following procedure shows interaction between a herbicide and antidote when the antidote is applied in a soil furrow containing crop seed and the herbicide is incorporated in a soil cover layer. Containers were filled and compacted with fumigated silt loam soil to a depth of about 1.3 cm from the top of the container. A first container was designated as an untreated control, a second container was designated as a herbicide control, and a third container was designated as a herbicide+antidote test container. Each container was seeded with crop seed in marked furrows. Antidote compound, dissolved in acetone, was applied directly to the seeded furrows of the third container. Antidote application rate was 0.55 mg active compound per inch of furrow (0.22 mg/cm). This rate was comparable to a plot application rate of 0.28 kilogram per hectare (kg/ha), based on 76 cm (30") spaced-apart furrows. Then, each of the second and third containers was filled and leveled with a cover layer of soil having incorporated therein the selected herbicide at a pre-determined concentration. The first container was filled and leveled with soil containing no herbicide. The containers were then placed on a bench in a greenhouse and sub-irrigated as required for the duration of the test. Plant response was observed about three weeks after initial treatment. Results are reported in Table 2.
TABLE 2__________________________________________________________________________% PLANT INHIBITION AND % SAFENING EFFECT ( )HERB. ANTIDOTE Sorghum Wheat Rice Soybean CornNO. RATE NO. RATE W WO W WO W WO W WO W WO__________________________________________________________________________1 .56 1 .28 90 95 (5)1 .56 2 .28 85 95 (10)1 .56 3 .28 95 95 (0)1 .56 4 .28 80 95 (15)1 .56 5 .28 80 95 (15)1 .56 13 .28 95 95 (0)1 .56 6 .28 95 100 (5)2 2.24 1 .28 25 95 15 60 (73) (75)2 2.24 2 .28 15 100 30 70 (85) (57)2 2.24 3 .28 55 95 85 100 (42) (15)2 2.24 4 .28 45 95 50 70 (52) (28)2 2.24 5 .28 15 95 10 65 (84) (84)2 2.24 13 .28 35 100 50 85 (65) (41)2 2.24 6 .28 35 95 90 95 (63) (5)2 2.24 27 .28 45 95 (52)2 2.24 7 .28 35 95 (63)2 2.24 28 .28 25 95 (73)2 2.24 8 .28 10 95 (89)2 2.24 29 .28 30 100 (70)2 2.24 14 .28 20 100 (80)2 2.24 30 .28 60 100 (40)2 2.24 15 .28 30 100 (70)2 2.24 16 .28 25 100 (75)2 2.24 9 .28 40 100 (60)2 2.24 10 .28 15 100 (85)2 2.24 11 .28 15 85 (82)2 2.24 17 .28 20 90 (77)2 2.24 20 .28 15 90 (83)2 2.24 12 .28 50 95 (47)2 2.24 18 .28 35 97 (63)2 2.24 24 .28 50 98 (48)2 2.24 19 .28 35 98 (64)2 2.24 22 .28 95 92 (0)3 4.48 1 .28 0 80 (100)3 4.48 2 .28 50 95 (47)3 4.48 3 .28 85 95 (10)3 4.48 4 .28 70 95 (26)3 4.48 5 .28 90 95 (5)3 4.48 13 .28 55 85 (35)3 4.48 6 .28 90 95 (5)4 2.24 1 .28 30 40 5 95 (25) (94)4 2.24 2 .28 30 70 10 95 (57) (89)4 2.24 3 .28 95 90 5 95 (0) (94)4 2.24 4 .28 70 80 15 80 (12) (81)4 2.24 5 .28 80 55 45 85 (0) (47)4 2.24 13 .28 40 55 35 90 (27) (61)4 2.24 6 .28 80 75 5 95 (0) (94)5 .07 1 .28 95 100 90 100 (5) (10)5 .14 1 .28 65 50 100 100 (0) (0)5 .07 2 .28 100 100 90 95 (0) (5)5 .14 2 .28 55 55 85 95 (0) (10)5 .07 3 .28 50 90 95 95 (44) (0)5 .14 3 .28 40 75 95 95 (46) (0)5 .07 4 .28 90 65 95 95 (0) (0)5 .14 4 .28 70 60 95 95 (0) (0)5 .07 5 .28 95 80 95 90 (0) (0)5 .14 5 .28 65 60 95 85 (0) (0)5 .07 13 .28 85 80 35 85 (0) (58)5 .14 13 .28 45 45 55 90 (0) (38)5 .07 6 .28 90 95 95 95 (5) (0)5 .14 6 .28 75 90 95 95 (16) (0)5 .07 27 .28 95 100 75 90 (5) (16)5 .14 27 .28 60 50 95 95 (0) (0)5 .07 7 .28 95 100 95 90 (5) (0)5 .14 7 .28 65 50 95 95 (0) (0)5 .07 28 .28 100 100 95 90 (0) (0)5 .14 28 .28 20 50 95 95 (60) (0)5 .07 8 .28 100 95 95 90 (0) (0)5 .14 8 .28 60 80 90 95 (25) (5)5 .07 29 .28 100 95 95 95 (0) (0)5 .14 29 .28 85 85 95 95 (0) (0)5 .07 14 .28 90 95 95 95 (5) (0)5 .14 14 .28 65 75 95 95 (13) (0)5 .07 30 .28 95 95 95 95 (0) (0)5 .14 30 .28 40 75 95 95 (46) (0)5 .07 15 .28 100 95 95 95 (0) (0)5 .14 15 .28 75 75 95 95 (0) (0)5 .07 16 .28 100 95 95 95 (0) (0)5 .14 16 .28 70 85 95 95 (17) (0)5 .07 9 .28 100 100 95 95 (0) (0)5 .14 9 .28 65 70 95 95 (7) (0)5 .07 10 .28 95 100 85 95 (5) (10)5 .14 10 .28 55 50 75 95 (0) (21)5 .07 11 .28 100 95 30 95 (0) (68)5 .14 11 .28 30 50 95 85 (40) (0)5 .07 17 .28 100 100 70 100 (0) (30)5 .14 17 .28 25 70 85 90 (64) (5)5 .07 20 .28 100 100 90 100 (0) (10)5 .14 20 .28 65 70 100 90 (7) (0)5 .07 12 .28 95 95 65 95 (0) (31)5 .14 12 .28 15 80 70 95 (81) (26)__________________________________________________________________________
EXAMPLE 40
The following procedure shows interaction between herbicide and antidote when both are incorporated in a soil cover layer before emergence of crop and weed species. Containers were filled and compacted with a fumigated silt loam top soil to a depth of about 1.3 cm from the top of the container. A first container was designated as an untreated control, a second container was designated as a herbicide control, and a third container was designated as a herbicide+antidote test container. Each of the containers was seeded with a crop species. A measured amount of herbicide dispersed or dissolved in acetone was applied to a measured quantity of soil. To this same quantity of soil treated with herbicide, there was added a measured amount of antidote dispersed or dissolved in aceton. The quantity of soil treated with the herbicide and antidote was thoroughly mixed to incorporate the herbicide and antidote in the soil uniformly. The seed bed in the third container of soil was covered with the soil treated with the herbicide and antidote and the container was leveled. For each test series, the seed beds of the first and second containers were likewise covered by soil layers. The cover layer of the first container was not treated with herbicide or antidote. The cover layer of the second container had a measured quantity of herbicide along incorporated therein. The containers were then placed on a bench in a greenhouse and sub-irrigated as required for the duration of the test. Plant response was observed about three weeks after initial treatment. Results are reported in Table 3.
TABLE 3 % PLANT INHIBITION AND % SAFENING EFFECT ( )ANTI- Barnyard Foxtail Wild HERB. DOTE Sorghum Wheat Corn Grass Rice Green Oats Soybean NO. RATE NO. RATE W WO W WO W WO W WO W WO W WO W WO W WO 6 .56 1 .56 85 95 95 95 (10) (0) 6 .56 1 2.24 80 95 95 95 (15) (0) 6 .56 1 8.96 75 95 75 95 (21) (21) 6 2.24 1 .56 100 100 100 100 (0) (0) 6 2.24 1 2.24 95 100 100 100 (5) (0) 6 2.24 1 8.96 95 100 95 100 (5) (5) 6 3.36 1 .56 95 100 70 40 (5) (0) 6 3.36 1 2.24 95 100 45 40 (5) (0) 6 3.36 1 8.96 95 100 70 40 (5) (0) 6 6.72 1 .56 95 100 15 82 (5) (81) 6 6.72 1 2.24 95 100 85 82 (5) (0) 6 6.72 1 8.96 95 100 50 82 (5) (39) 6 .56 3 .56 85 95 95 95 (10) (0) 6 .56 3 2.24 85 95 95 95 (10) (0) 6 .56 3 8.96 75 95 85 95 (21) (10) 6 2.24 3 .56 95 100 100 100 (5) (0) 6 2.24 3 2.24 95 100 95 100 (5) (5) 6 2.24 3 8.96 95 100 95 100 (5) (5) 6 3.36 3 .56 95 100 70 40 (5) (0) 6 3.36 3 2.24 95 100 30 40 (5) (25) 6 3.36 3 8.96 95 100 75 40 (5) (0) 6 6.72 3 .56 95 100 0 82 (5) (100) 6 6.72 3 2.24 95 100 70 82 (5) (14) 6 6.72 3 8.96 100 100 70 82 (0) (14) 6 .56 20 .56 75 95 95 95 (21) (0) 6 .56 20 2.24 70 95 95 95 (26) (0) 6 .56 20 8.96 75 95 95 95 (21) (0) 6 2.24 20 .56 95 100 100 100(5) (0) 6 2.24 20 2.24 95 100 95 100 (5) (5) 6 2.24 20 8.96 95 100 100 100 (5) (0) 6 3.36 20 .56 95 100 70 40 (5) (0) 6 3.36 20 2.24 9 5 100 0 40 (5) (100) 6 3.36 20 8.96 95 100 60 40(5) (0) 6 6.72 20 .56 100 100 100 82 (0) (0) 6 6.72 20 2.24 95 100 30 82 (5) (63) 6 6.72 20 8.96 95 100 50 82 (5) (39) 1 .28 1 .56 95 95 100 100(0) (0) 1 .28 1 2.24 95 95 100 100 (0)(0) 1 .28 1 8.96 90 95 100 100 (5) (0) 1 1.12 1 .56 100 100 100 100 (0) (0) 1 1.12 1 2.24 100 100 100 100 (0) (0) 1 1.12 1 8.96 95 100 100 100 (5) (0) 1 .28 3 .56 95 95 100 100 (0) (0) 1 .28 3 2.24 95 95 100 100 (0) (0) 1 .28 3 8.96 90 95 100 100 (5) (0) 1 1.12 3 .56 95 100 100 100 (5) (0) 1 1.12 3 2.24 100 100 100 100 (0) (0) 1 1.12 3 8.96 100 100 100 100 (0) (0) 1 .28 20 .56 90 95100 100 (5) (0) 1 .28 20 2.24 70 95 100 100 (26) (0) 1 .28 20 8.96 95 95 100 100 ( 0) (0) 1 1.12 20 .56 95 100 100 100 (5) (0) 1 1.12 20 2.24 100 100 100 100 (0) (0) 1 1.12 20 8.96 95 100 100 100 (5) (0) 2 .56 1 .14 70 97 100 100 (27) (0) 2 .56 1 .14 50 42 100 100 (0) (0) 2 .56 1 .14 5 53 98 95 (90) (0) 2 .56 1 .14 45 97 100 100 (53) (0) 2 .56 1 .14 5 25 100 98 (80) (0) 2 .56 1 .14 40 32 100 100 (0) (0) 2 .56 1 .56 0 42 100 100 (100) (0) 2 .56 1 .56 10 25 98 98 (60) (0) 2 .56 1 .56 10 53 95 95 (81) (0) 2 .56 1 .56 70 97 100 100 (27) (0) 2 .56 1 .56 10 32 100 100 (68) (0) 2 .56 1 .56 15 97 100 100 (84) (0) 2 .56 1 .56 15 90 95 100 (83) (5) 2 .56 1 .56 60 90 95 100 (33) (5) 2 .56 1 .56 0 95 100 100 (100) (0) 2 .56 1 .56 0 77 100 100 (100) (0) 2 .56 1 .56 20 60 95 100 (66) (5) 2 .56 1 .56 20 83 100 98 (75) (0) 2 .56 1 .56 10 93 1 00 100 (89) (0) 2 .56 1 .56 10 60 95 100 (83) (5) 2 .56 1 .56 25 90 95 95 (72) (0) 2 .56 1 .56 5 80 95 100 (93) (5) 2 .56 1 .56 0 93 100 100 (100) (0) 2 .56 1 .56 5 75 100 100 (93) (0) 2 .56 1 .56 15 35 95 90 (57) (0) 2 .56 1 .56 10 95 100 100 (89) (0) 2 .56 1 .56 20 65 100 95 (69) (0) 2 .56 1 .56 5 85 100 100(94) (0) 2 .56 1 .56 5 95 95 100 (94) (5) 2 .56 1 .56 10 85 100 100 (88) (0) 2 .56 1 .56 55 95 100 100 (42) (0) 2 .56 1 .56 25 95 100 100 (73) (0) 2 .56 1 .56 10 70 95 100 (85) (5) 2 .56 1 .56 10 90 95 95 (88) (0) 2 .56 1 .56 15 80 95 95 (81) (0) 2 .56 1 .56 5 90 9 5 100 (94) (5) 2 .56 1 .56 10 80 95 100 (87) (5) 2 .56 1 .56 15 95 95 100 (84) (5) 2 .56 1 .56 30 28 95 95 (0) (0) 2 .56 1 .56 20 85 95 100 (76) (5) 2 .56 1 .56 30 95 100 100 (68) (0) 2 .56 1 .56 10 30 95 95 (66) (0) 2 .56 1 .56 20 55 95 95 (63) (0) 2 .56 1 .56 0 95 1 00 100 (100) (0) 2 .56 1 .56 10 70 95 100 (85) (5) 2 .56 1 .56 35 95 100 100 (63) (0) 2 .56 1 .56 5 95 100 100 (94) (0) 2 .56 1 .56 15 80 95 100 (81) (5) 2 .56 1 .56 25 95 100 100 (73) (0) 2 .56 1 .56 45 85 100 95 (47) (0) 2 .56 1 .56 25 75 100 95 (66) (0) 2 .56 1 .56 30 90 95 100 (66) (5) 2 .56 1 .56 65 93 100 100 (30) (0) 2 .56 1 .56 30 95 100 100 (68) (0) 2 .56 1 .56 0 85 100 100 (100) (0) 2 .56 1 2.24 30 97 100 100 (69) (0) 2 .56 1 2.24 20 32 98 100 (37) (2) 2 .56 1 2.24 0 53 95 95 (100) (0) 2 .56 1 2.24 25 25 98 98 (0) (0) 2 .56 1 2.24 30 42 100 100 (28) (0) 2 .56 1 2.24 40 95 100 100 (57) (0) 2 .56 1 2.24 55 97 100 100 (43) (0) 2 .56 1 2.24 15 90 100 100 (83) (0) 2 .56 1 2.24 20 90 85 100 (77) (15) 2 .56 1 2.24 20 95 100 100 (78) (0) 2 .56 1 2.24 50 93 100 100 (46) (0) 2 .56 1 2.24 30 75 95 95 (60) (0) 2 .56 1 2.24 20 95 100 100 (78) (0) 2 .56 1 2.24 35 70 100 100 (50) (0) 2 .56 1 2.24 15 90 95 95 (83) (0) 2 .56 1 2.24 10 80 95 100 (87) (5) 2 .56 1 2.24 30 85 95 95 (64) (0) 2 .56 1 2.24 35 95 95 100 (63) (5) 2 .56 1 2.24 40 85 100 100 (52) (0) 2 .56 1 2.24 5 95 100 100 (94) (0) 2 .56 1 2.24 30 95 100 100 ( 68) (0) 2 .56 1 2.24 10 30 90 95 (66) (5) 2 .56 1 2.24 20 90 100 100 (77) (0) 2 .56 1 2.24 15 95 95 100 (84) (5) 2 .56 1 2.24 35 55 95 95(36) (0) 2 .56 1 2.24 15 85 90 100 (82) (10) 2 .56 1 2.24 20 28 100 95 (28) (0) 2 .56 1 2.24 15 80 100 100 (81) (0) 2 .56 1 2.24 40 95 100 100 (57) (0) 2 .56 1 2.24 5 80 95 95 (93) (0) 2 .56 1 2.24 0 93 100 100 (100) (0) 2 .56 1 2.24 15 90 95 100 (83) (5) 2 .56 1 2.24 5 85 100 100 (94) (0) 2 .56 1 2.24 35 70 90 100 (50) (10) 2 .56 1 2.24 30 95 100 100 (68) (0) 2 .56 1 2.24 5 95 95 100 (94) (5) 2 .56 1 2.24 15 100 100 100 (85) (0) 2 .56 1 2.24 5 75 100 100 (93) (0) 2 .56 1 2.24 20 80 100 100 (75) (0) 2 .56 1 2.24 20 65 95 95 (69)(0) 2 .56 1 2.24 10 60 100 100 (83) (0) 2 .56 1 2.24 0 83 100 98 (100) (0) 2 .56 1 2.24 20 95 95 100 (78) (5) 2 .56 1 2.24 0 95 100 100 (100) (0) 2 .56 1 2.24 15 35 90 90 (57) (0) 2 .56 1 2.24 30 90 95 95 (66) (0) 2 .56 1 2.24 15 85 95 100 (82) (5) 2 .56 1 2.24 0 93 100 100 (100) (0) 2 .56 1 2.24 0 77 100 100 (100) (0) 2 .56 1 2.24 25 60 95 100 (58) (5) 2 .56 1 8.96 0 95 100 100 (100) (0) 2 .56 1 8.96 25 60 90 100 (58) (10) 2 .56 1 8.96 0 85 95 100 (100) (5) 2 .56 1 8.96 10 35 100 90 (71) (0) 2 .56 1 8.96 20 77 100 100 (74) (0) 2 .56 1 8.96 10 95 100 100 (89) (0) 2 .56 1 8.96 10 95 95 100 (89) (5) 2 .56 1 8.96 0 93 95 100 (100) (5) 2 .56 1 8.96 5 65 100 95 (92) (0) 2 .56 1 8.96 10 70 100 100 (85) (0) 2 .56 1 8.96 10 75 90 100 (86) (10) 2 .56 1 8.96 5 85 95 100 (94) (5) 2 .56 1 8.96 30 95 100 100 (68) (0) 2 .56 1 8.96 50 55 95 95 (9) (0) 2 .56 1 8.96 30 80 95 100 (62) (5) 2 .56 1 8.96 10 28 90 95 (64) (5) 2 .56 1 8.96 0 90 95 100 (100) (5) 2 .56 1 8.96 15 95 95 100 (84) (5) 2 .56 1 8.96 10 80 90 100 (87) (10) 2 .56 1 8.96 15 70 100 100 (78) (0) 2 .56 1 8.96 5 90 95 95(94) (0) 2 .56 1 8.96 30 93 100 100 (67) (0) 2 .56 1 8.96 10 75 100 95 (86) (0) 2 .56 1 8.96 20 95 95 100 (78) (5) 2 .56 1 8.96 25 90 95 100 (72) (5) 2 .56 1 8.96 15 90 95 100 (83) (5) 2 .56 1 8.96 30 85 95 95 (64) (0) 2 .56 1 8.96 15 30 95 95 (50) (0) 2 .56 1 8.96 30 95 95 100 (68) (5) 2 .56 1 8.96 10 100 80 100 (90) (20) 2 .56 1 8.96 0 80 85 95 (100) (10) 2 .56 1 8.96 20 95 95 100 (78) (5) 2 .56 1 8.96 20 95 95 100 (78) (5) 2 .56 1 8.96 0 85 95 100 (100) (5) 2 .56 1 8.96 25 95 100 100 (73) (0) 2 .56 1 8.96 20 80 95 100 (75) (5) 2 .56 1 8.96 20 83 95 98 (75) (3) 2 .56 1 8.96 10 95 100 100 (89) (0) 2 .56 1 8.96 20 90 95 95 (77) (0) 2 .56 1 8.96 0 95 95 100 (100) (5) 2 .56 1 8.96 10 90 95 100 (88) (5) 2 .56 1 8.96 10 60 90 100 (83) (10) ##STR43##
14 .56 3 .56 40 73 95 98 (45) (3) 14 .56 3 2.24 15 73 100 98 (79) (0) 14 .56 3 8.96 15 73 100 98 (79) (0) 14 2.24 3 .56 75 95 100 100 (21) (0) 14 2.24 3 2.24 55 95 100 100 (42) (0) 14 2.24 3 8.96 35 95 100 100 (63) (0) 14 .56 20 .56 5 73 100 98 (93) (0) 14 .56 20 2.24 5 73 95 98 (93) (3) 14 .56 20 8.96 0 73 100 98 (100) (0) 14 2.24 20 .56 30 95 100 100 (68) (0) 14 2.24 20 2.24 15 95 100 100 (84) (0) 14 2.24 20 8.96 40 95 100 100 (57) (0) 4 .56 1 .56100 100 40 65 (0) (38) 4 .56 1 .56 80 97 100 100(17) (0) 4 .56 1 2.24 100 100 15 65 (0) (76) 4 .56 1 2.24 25 97 100 100 (74) (0) 4 .56 1 2.24 100 100 25 95 (0) (73) 4 .56 1 8.96 15 97 100 100 (84) (0) 4 .56 1 8.96 100 100 50 65 (0) (23) 4 .56 1 8.96 100 100 5 95 (0) (94) 4 2.24 1 .56 100 100 65 70 (0) (7) 4 2.24 1 .56 95 100 100 100 (5) (0) 4 2.24 1 2.24 85 100 100 100 (15) (0) 4 2.24 1 2.24 100 100 90 70 (0) (0) 4 2.24 1 2.24 100 100 30 100 (0) (70) 4 2.24 1 8.96 80 100 100 100 (20) (0) 4 2.24 1 8.96 100 100 15 70 (0) (78) 4 2.24 1 8.96 100 100 5 100 (0) (95) 4 .56 2 .56 100 100 15 80 (0) (81) 4 .56 2 2.24 100 100 5 80 (0) (93) 4 .56 2 8.96 100 100 0 80 (0) (100) 4 1.12 2 .56 100 100 40 55 (0) (27) 4 1.12 2 2.24 100 100 35 55 (0) (36) 4 1.12 2 8.96 100 100 45 55 (0) (18) 4 2.24 2 .56 100 100 15 95 (0) (84) 4 2.24 2 2.24 100 100 5 95 (0) (94) 4 2.24 2 8.96 100 100 5 95 (0) (94) 4 4.48 2 .56 100 100 70 80 (0) (12) 4 4.48 2 2.24 100 100 80 80 ( 0) (0) 4 4.48 2 8.96 100 100 70 80 (0) (12) 4 .56 3 .56 80 97 100 100 (17) (0) 4 .56 3 .56 100 100 0 65 (0) (100) 4 .56 3 .56 100 100 0 70 (0) (100) 4 .56 3 2.24 100 100 0 65 (0) ( 100) 4 .56 3 2.24 85 97 100 100 (12) (0) 4 .56 3 2.24 100 100 0 70 (0) (100) 4 .56 3 8.96 70 97 1 00 100 (27) (0) 4 .56 3 8.96 100 100 0 65 (0) (100) 4 .56 3 8.96 95 100 15 70 (5) (78) 4 2.24 3 .56 95 100 54 100 (5) (46) 4 2.24 3 .56 100 100 0 70 (0) (100) 4 2.24 3 .56 100 100 10 90 (0) (88) 4 2.24 3 2.24 95 100 100 100 (5) (0) 4 2.24 3 2.24 100 100 0 70 (0) (100) 4 2.24 3 2.24 100 100 0 90 (0) (100) 4 2.24 3 8.96 100 100 5 70 (0) (92) 4 2.24 3 8.96 90 100 100 100 (10) (0) 4 2.24 3 8.96 95 100 10 90 (5) (88) 4 .56 4 .56 100 100 0 70 (0) (100) 4 .56 4 2.24 1 00 100 0 70 (0) (100) 4 .56 4 8.96 100 100 0 70 (0) (100) 4 2.24 4 .56 100 100 10 90 (0) (88) 4 2.24 4 2.24 100 100 15 90 (0) (83) 4 2.24 4 8.96 95 100 5 90 (5) (94) 4 .56 5 .56 100 100 30 75 (0) (60) 4 .56 5 2.24 100 100 15 75 (0) (80) 4 .56 5 8.96 100 100 15 75 (0) (80) 4 2.24 5 .56 100 100 35 95 (0) (63) 4 2.24 5 2.24 100 100 10 95 (0) (89) 4 2.24 5 8.96 100 100 10 95 (0) (89) 4 .56 13 .56 100 100 5 85 (0) (94) 4 .56 13 2.24 100 100 5 85 (0) (94) 4 .56 13 8.96 100 100 0 85 (0) (100) 4 2.24 13 .56 100 100 65 95 (0) (31) 4 2.24 13 2.24 100 100 10 95 (0) (89) 4 2.24 13 8.96 100 100 5 95 (0) (94) 4 .56 20 .56 60 97 100 100 (38) (0) 4 .56 20 .56 100 100 20 65 (0) (69) 4 .56 20 2.24 100 100 55 65 (0) (15) 4 .56 20 2.24 40 97 100 100 (58) (0) 4 .56 20 8.96 100 100 20 65 (0) (69) 4 .56 20 8.96 10 97 100 100 (89) (0) 4 2.24 20 .56 85 100 100 100 ( 15) (0) 4 2.24 20 .56 100 100 30 70 (0) (57) 4 2.24 20 2.24 60 100 100 100 (40) (0) 4 2.24 20 2.24 100 100 70 70 (0) (0) 4 2.24 20 8.96 100 100 25 70 (0) (64) 4 2.24 20 8.96 60 100 100 100 (40) (0) 10 2.24 1 .56 100 100 30 95 (0) (68) 10 2.24 1 2.24 100 100 50 95 (0) (47) 10 2.24 1 8.96 100 100 50 95 (0) (47) 10 8.96 1 .56 100 100 90 85 (0) (0) 10 8.96 1 2.24 100 100 40 85 (0) (52) 10 8.96 1 8.96 100 100 30 85 (0) (64) 10 2.24 3 .56 100 100 10 95 (0) (89) 10 2.24 3 2.24 100 100 10 95 (0) (89) 10 2.24 3 8.96 100 100 5 95 (0) (94) 10 8.96 3 .56 100 100 15 85 (0) (82) 10 8.96 3 2.24 100 100 75 85 (0) (11) 10 8.96 3 8.96 100 100 60 85 (0) (29) 10 2.24 20 .56 100 100 25 95 (0) (73) 10 2.24 20 2.24 100 100 45 95 (0) (52) 10 2.24 20 8.96 100 100 30 95 (0) (68) 10 8.96 20 .56 100 100 85 85 (0) (0) 10 8.96 20 2.24 100 100 90 85 (0) (0) 10 8.96 20 8.96 100 100 85 85 (0) (0) 11 .56 1 .56 40 93 100 100 (56) (0) 11 .56 1 2.24 60 93 100 100 (35) (0) 11 .56 1 8.96 0 93 95 100 (100) (5) 11 2.24 1 .56 100 100 20 60 (0) (66) 11 2.24 1 .56 95 98 100 100 (3) (0) 11 2.24 1 2.24 85 98 100 100 (13) (0) 11 2.24 1 2.24100 100 35 60 (0) (41) 11 2.24 1 8.96 100 100 60 60 (0) (0) 11 2.24 1 8.96 90 98 100 100 (8) ( 0) 11 8.96 1 .56 100 100 30 97 (0) (69) 11 8.96 1 2.24 100 100 65 97 (0) (32) 11 8.96 1 8.96 100 100 35 97 (0) (63) 11 .56 3 .56 50 93 100 100 (46) (0) 11 .56 3 2.24 40 93 100 100 (56) (0) 11 .56 3 8.96 60 93 95 100 (35) (5) 11 2.24 3 .56 95 98 100 100 (3) (0) 11 2.24 3 .56 100 100 0 60(0) (100) 11 2.24 3 2.24 100 100 0 60 (0) (100) 11 2.24 3 2.24 95 98 100 100 (3) (0) 11 2.24 3 8.96 100 100 0 60 (0) (100) 11 2.24 3 8.96 95 98 100 100 (3) (0) 11 8.96 3 .56 100 100 0 97 (0) ( 100) 11 8.96 3 2.24 100 100 5 97 (0) (94) 11 8.96 3 8.96 100 100 0 97 (0) (100) 11 .56 20 .56 60 93 100 100 (35) (0) 11 .56 20 2.24 40 93 100 100 ( 56) (0) 11 .56 20 8.96 40 93 95 100 (56) (5) 11 2.24 20 .56 85 98 100 100 (13) (0) 11 2.24 20 .56 100 100 0 60 (0) (100) 11 2.24 20 2.24 85 98 100 100 (13) (0) 11 2.24 20 2.24 100 100 55 60 (0) (8) 11 2.24 20 8.96 100 100 40 60 (0) (33) 11 2.24 20 8.96 75 98 100 100 (23) (0) 11 8.96 20 .56 100 100 70 97 (0) (27) 11 8.96 20 2.24 100 100 75 97 (0) (22) 11 8.96 20 8.96 100 100 45 97 (0) (53) 5 .03 3 .56 60 95 95 85 (36) (0) 5 .03 3 2.24 95 95 90 85 (0) (0) 5 .03 3 8.96 30 95 100 85 (68) (0) 5 .07 3 .56 100 10095 95 (0) (0) 5 .07 3 2.24 80 100 95 95 (20) (0) 5 .07 3 8.96 100 100 100 95 (0) (0) 5 .03 13 .56 95 95 100 100 (0) (0) 5 .03 13 2.24 95 95 100 100 (0) (0) 5 .03 13 8.96 95 95 100 100 (0) (0) 5 .07 13 .56 95 100 100 100 (5) (0) 5 .07 13 2.24 95 100 100 100 (5) (0) 5 .07 13 8.96 95 100 100 100 (5) (0) 12 .56 1 .56 60 65 100 100 (7) ( 0) 12 .56 1 2.24 65 65 100 100 (0) (0) 12 .56 1 8.96 55 65 100 100 (15) (0) 12 2.24 1 .56 100 100 100 100 (0) (0) 12 2.24 1 .56 100 100 90 72 (0) (0) 12 2.24 1 2.24 100 100 100 100 (0) (0) 12 2.24 1 2.24 100 100 75 72 (0) (0) 12 2.24 1 8.96 100 100 80 72 (0) (0) 12 2.24 1 8.96 95 100 100 100 (5) (0) 12 4.48 1 .56 100 100 80 85 (0) (5) 12 4.48 1 2.24 100 100 90 85 (0) (0) 12 4.48 1 8.96 100 100 85 85 (0) (0) 12 .56 3 .56 65 65 100 100 (0) (0) 12 .56 3 2.24 50 65 100 100 (23) (0) 12 .56 3 8.96 95 65 100 100 (0) (0) 12 2.24 3 .56 95 100 100 100 (5) (0) 12 2.24 3 .56 100 100 70 72 (0) (2) 12 2.24 3 2.24 100 100 10 100 (0) (90) 12 2.24 3 2.24 100 100 70 72 (0) (2) 12 2.24 3 8.96 100 100 85 72 (0) (0) 12 2.24 3 8.96 95 100 100 100 (5) (0) 12 4.48 3 .56 100 100 75 85 (0) (11) 12 4.48 3 2.24 100 100 80 85 (0) (5) 12 4.48 3 8.96 100 100 70 85 (0) (17) 12 .56 20 .56 30 65 100 100 (53) (0) 12 .56 20 2.24 65 65 100 100 (0) (0) 12 .56 20 8.96 55 65 1 00 100 (15) (0) 12 2.24 20 .56 100 100 80 72 (0) (0) 12 2.24 20 .56 95 100 100 100 (5) (0) 12 2.24 20 2.24 100 100 75 72 (0) (0) 12 2.24 20 2.24 9 5 100 100 100 (5) (0) 12 2.24 20 8.96 100 100 75 72 (0) (0) 12 2.24 20 8.96 85 100 100 100 ( 15) (0) 12 4.48 20 .56 100 100 80 85 (0) (5) 12 4.48 20 2.24 100 100 80 85 (0) (5) 12 4.48 20 8.96 100 100 85 85 (0) (0)
EXAMPLE 41
The following procedure shows interaction between herbicide and antidote when applied together as a mixture before emergence of the crop and weed species. Containers were filled and compacted with fumigated silt loam top soil to a depth of about 1.3 cm from the top of the container. A first container was designated as an untreated control, a second container was designated as a herbicide control, and a third container was designated as a herbicide+antidote test container. Each of the containers was seeded with both crop plant and weed species. The herbicide and the herbicide+antidote test mixture were applied to the seeded containers either by a procedure of topical application to a soil layer placed over the seed bed followed by watering to achieve incorporation, or by a procedure of incorporation into soil and then placement of the treated soil into the container over the seed bed. The containers were then placed on a greenhouse bench, and sub-irrigated as required for the duration of the test. Plant response was observed about three weeks after initial treatment. Results are reported in Table 4.
TABLE 4__________________________________________________________________________% PLANT INHIBITION AND % SAFENING EFFECT ( ) Foxtail Crabgrass BarnyardHERB. ANTIDOTE Sorghum Green Large Grass CornNO. RATE NO. RATE W WO W WO W WO W WO W WO__________________________________________________________________________2 .56 1 .03 60 87 98 100 100 100 (31) (2) (0)2 .56 1 .03 20 37 100 100 100 100 (45) (0) (0)2 .56 1 .07 25 95 100 100 100 100 (73) (0) (0)2 .56 1 .14 13 78 100 100 95 95 (83) (0) (0)2 .56 1 .14 15 90 100 100 95 95 (83) (0) (0)2 .56 1 .14 10 77 100 100 100 100 (87) (0) (0)2 .56 1 .14 23 90 95 95 100 100 (74) (0) (0)2 .56 1 .14 20 87 100 100 100 100 (77) (0) (0)2 .56 1 .14 10 70 (85)2 .56 1 .14 13 83 (84)2 .56 1 .14 5 95 100 100 100 100 (94) (0) (0)2 .56 1 .14 10 92 100 100 100 100 (89) (0) (0)2 .56 1 .14 43 37 100 100 100 100 (0) (0) (0)2 .56 1 .14 18 93 100 90 100 100 (80) (0) (0)2 .56 1 .56 0 78 98 100 98 95 100) (2) (0)2 .56 1 .56 20 77 100 100 100 100 (74) (0) (0)2 .56 1 .56 18 92 100 100 100 100 (80) (0) (0)2 .56 1 .56 15 37 98 100 98 100 (59) (2) (2)2 .56 1 .56 8 95 100 100 100 100 (91) (0) (0)2 .56 1 .56 0 93 95 90 95 100 (100) (0) (5)2 .56 1 .56 48 95 100 100 98 100 (49) (0) (2)2 .56 1 .56 13 70 (81)2 .56 1 .56 0 87 100 100 100 100 (100) (0) (0)2 .56 1 .56 8 83 (90)2 .56 1 .56 8 90 85 95 100 100 (91) (10) (0)2 .56 1 .56 30 90 100 100 100 95 (66) (0) (0)2 .56 1 1.12 8 95 100 100 100 100 (91) (0) (0)2 .56 1 2.24 18 93 95 90 100 100 (80) (0) (0)2 .56 1 2.24 10 92 100 100 100 100 (89) (0) (0)2 .56 1 2.24 5 70 (92)2 .56 1 2.24 5 77 100 100 100 100 (93) (0) (0)2 .56 1 2.24 5 83 (93)2 .56 1 2.24 13 95 100 100 100 100 (86) (0) (0)2 .56 1 2.24 5 78 100 100 100 95 (93) (0) (0)2 .56 1 2.24 13 90 85 95 100 100 (85) (10) (0)2 .56 1 2.24 23 90 100 100 100 95 (74) (0) (0)2 1.12 1 .03 83 95 100 100 100 100 (12) (0) (0)2 1.12 1 .03 83 65 100 100 100 100 (0) (0) (0)2 1.12 1 .07 28 95 100 100 100 100 (70) (0) (0)2 1.12 1 .14 33 65 100 100 100 100 (49) (0) (0)2 1.12 1 .14 8 98 100 100 100 100 (91) (0) (0)2 1.12 1 .14 28 90 100 100 100 100 (68) (0) (0)2 1.12 1 .14 33 95 95 98 100 100 (65) (3) (0)2 1.12 1 .14 43 95 100 100 100 100 (54) (0) (0)2 1.12 1 .14 28 95 95 95 100 100 (70) (0) (0)2 1.12 1 .14 40 95 100 100 100 100 (57) (0) (0)2 1.12 1 .14 8 85 (90)2 1.12 1 .14 20 85 (76)2 1.12 1 .14 53 93 100 100 100 100 (43) (0) (0)2 1.12 1 .14 28 95 100 100 100 100 (70) (0) (0)2 1.12 1 .56 8 85 (90)2 1.12 1 .56 8 95 100 100 100 100 (91) (0) (0)2 1.12 1 .56 13 85 (84)2 1.12 1 .56 18 95 100 100 100 100 (81) (0) (0)2 1.12 1 .56 13 90 100 100 100 100 (85) (0) (0)2 1.12 1 .56 5 98 100 100 98 100 (94) (0) (2)2 1.12 1 .56 33 95 100 100 100 100 (65) (0) (0)2 1.12 1 .56 43 100 100 100 100 100 (57) (0) (0)2 1.12 1 .56 25 65 100 100 100 100 (61) (0) (0)2 1.12 1 .56 25 95 100 95 100 100 (73) (0) (0)2 1.12 1 .56 18 95 95 98 100 100 (81) (3) (0)2 1.12 1 .56 30 93 100 100 100 100 (67) (0) (0)2 1.12 1 1.12 53 100 100 100 100 100 (47) (0) (0)2 1.12 1 2.24 8 95 100 100 100 100 (91) (0) (0)2 1.12 1 2.24 28 93 100 100 100 100 (69) (0) (0)2 1.12 1 2.24 5 90 100 100 100 100 (94) (0) (0)2 1.12 1 2.24 18 95 95 95 95 100 (81) (0) (5)2 1.12 1 2.24 5 85 (94)2 1.12 1 2.24 5 98 100 100 98 100 (94) (0) (2)2 1.12 1 2.24 70 100 100 100 100 100 (30) (0) (0)2 1.12 1 2.24 35 95 98 98 100 100 (63) (0) (0)2 1.12 1 2.24 20 85 (76)2 2.24 1 .03 85 90 100 100 100 100 (5) (0) (0)2 2.24 1 .03 95 97 100 100 100 100 (2) (0) (0)2 2.24 1 .07 60 99 100 100 100 100 (39) (0) (0)2 2.24 1 .14 93 97 100 100 100 100 (4) (0) (0)2 2.24 1 .14 70 98 100 100 98 100 (28) (0) (2)2 2.24 1 .14 38 98 98 98 100 100 (61) (0) (0)2 2.24 1 .14 75 99 100 100 100 100 (24) (0) (0)2 2.24 1 .14 40 95 95 100 100 100 (57) (5) (0)2 2.24 1 .14 73 97 100 100 100 100 (24) (0) (0)2 2.24 1 .14 40 97 100 100 100 100 (58) (0) (0)2 2.24 1 .14 18 93 98 100 100 100 (80) (2) (0)2 2.24 1 .14 33 78 (57)2 2.24 1 .14 55 90 100 100 100 100 (38) (0) (0)2 2.24 1 .14 35 90 (61)2 2.24 1 .56 78 90 100 100 100 100 (13) (0) (0)2 2.24 1 .56 20 98 100 100 100 100 (79) (0) (0)2 2.24 1 .56 33 98 100 98 100 100 (66) (0) (0)2 2.24 1 .56 33 90 (63)2 2.24 1 .56 15 97 100 100 100 100 (84) (0) (0)2 2.24 1 .56 23 95 100 100 100 100 (75) (0) (0)2 2.24 1 .56 75 97 100 100 100 100 (22) (0) (0)2 2.24 1 .56 38 97 100 100 100 100 (60) (0) (0)2 2.24 1 .56 5 78 (93)2 2.24 1 .56 93 100 100 100 100 100 (7) (0) (0)2 2.24 1 .56 8 93 100 100 100 100 (91) (0) (0)2 2.24 1 .56 13 99 100 100 100 100 (86) (0) (0)2 2.24 1 1.12 70 100 100 100 100 100 (30) (0) (0)2 2.24 1 2.24 63 100 100 100 100 100 (37) (0) (0)2 2.24 1 2.24 28 97 100 100 100 100 (71) (0) (0)2 2.24 1 2.24 0 78 (100)2 2.24 1 2.24 28 98 100 100 100 100 (71) (0) (0)2 2.24 1 2.24 33 93 100 100 100 100 (64) (0) (0)2 2.24 1 2.24 25 97 100 100 100 100 (74) (0) (0)2 2.24 2.24 40 95 100 100 100 100 (57) (0) (0)2 2.24 1 2.24 33 90 (63)2 2.24 1 2.24 28 98 100 98 100 100 (71) (0) (0)2 .56 2 .07 5 58 98 100 100 100 (91) (2) (0)2 .56 2 .14 15 58 100 100 100 100 (74) (0) (0)2 .56 2 .14 13 77 100 100 100 100 (83) (0) (0)2 .56 2 .14 35 95 100 100 100 100 (63) (0) (0)2 .56 2 .14 38 87 100 100 100 100 (56) (0) (0)2 .56 2 .14 5 92 100 100 100 100 (94) (0) (0)2 .56 2 .14 33 90 95 100 95 95 (63) (5) (0)2 .56 2 .56 10 58 100 100 100 100 (82) (0) (0)2 .56 2 .56 5 77 100 100 100 100 (93) (0) (0)2 .56 2 .56 30 87 98 100 100 100 (65) (2) (0)2 .56 2 .56 13 95 100 100 100 100 (86) (0) (0)2 .56 2 .56 43 92 100 100 100 100 (53) (0) (0)2 .56 2 .56 15 90 95 100 100 95 (83) (5) (0)2 .56 2 2.24 8 77 100 100 100 100 (89) (0) (0)2 .56 2 2.24 18 87 98 100 100 100 (79) (2) (0)2 .56 2 2.24 15 95 100 100 100 100 (84) (0) (0)2 .56 2 2.24 58 92 100 100 100 100 (36) (0) (0)2 .56 2 2.24 33 90 98 100 95 95 (63) (2) (0)2 1.12 2 .07 13 72 100 98 100 100 (81) (0) (0)2 1.12 2 .14 5 90 100 100 100 100 (94) (0) (0)2 1.12 2 .14 23 72 100 98 100 100 (68) (0) (0)2 1.12 2 .14 63 98 100 100 100 100 (35) (0) (0)2 1.12 2 .14 48 100 100 100 100 100 (52) (0) (0)2 1.12 2 .14 30 93 100 100 98 100 (67) (0) (2)2 1.12 2 .14 20 95 100 100 100 100 (78) (0) (0)2 1.12 2 .56 0 72 100 98 100 100 (100) (0) (0)2 1.12 2 .56 10 90 100 100 100 100 (88) (0) (0)2 1.12 2 .56 18 93 100 100 100 100 (80) (0) (0)2 1.12 2 .56 70 98 100 100 100 100 (28) (0) (0)2 1.12 2 .56 45 95 100 100 100 100 (52) (0) (0)2 1.12 2 .56 23 100 100 100 100 100 (77) (0) (0)2 1.12 2 2.24 0 90 100 100 100 100 (100) (0) (0)2 1.12 2 2.24 45 100 100 100 100 100 (55) (0) (0)2 1.12 2 2.24 35 98 100 100 100 100 (64) (0) (0)2 1.12 2 2.24 33 93 100 100 100 100 (64) (0) (0)2 1.12 2 2.24 30 95 100 100 100 100 (68) (0) (0)2 2.24 2 .07 60 97 100 100 100 100 (38) (0) (0)2 2.24 2 .14 25 97 100 100 100 100 (74) (0) (0)2 2.24 2 .14 45 97 100 100 100 100 (53) (0) (0)2 2.24 2 .14 25 98 100 100 100 100 (74) (0) (0)2 2.24 2 .14 78 97 100 100 100 100 (19) (0) (0)2 2.24 2 .14 88 98 100 100 100 100 (10) (0) (0)2 2.24 2 .14 53 100 100 100 100 100 (47) (0) (0)2 2.24 2 .56 23 97 100 100 100 100 (76) (0) (0)2 2.24 2 .56 8 97 100 100 100 100 (33) (0) (0)2 2.24 2 .56 23 97 100 100 100 100 (76) (0) (0)2 2.24 2 .56 63 100 100 100 100 100 (37) (0) (0)2 2.24 2 .56 43 98 100 100 100 100 (56) (0) (0)2 2.24 2 2.24 25 97 100 100 100 100 (74) (0) (0)2 2.24 2 2.24 45 100 100 100 100 100 (55) (0) (0)2 2.24 2 2.24 15 97 100 100 100 100 (84) (0) (0)2 2.24 2 2.24 25 98 100 100 100 100 (74) (0) (0)2 2.24 2 2.24 58 98 100 100 100 100 (40) (0) (0)2 .56 3 .03 60 37 98 100 100 100 (0) (2) (2)2 .56 3 .03 35 87 100 100 100 100 (59) (0) (0)2 .56 3 .04 5 88 98 100 95 100 (94) (2) (5)2 .56 3 .07 43 95 98 100 100 100 (54) (2) (0)2 .56 3 .07 45 58 98 100 100 100 (22) (2) (0)2 .56 3 .14 15 77 100 100 100 100 (80) (0) (0)2 .56 3 .14 8 88 98 100 98 100 (90) (0) (0)2 .56 3 .14 25 37 100 100 98 100 (32) (0) (2)2 .56 3 .14 30 87 100 100 100 100 (65) (0) (0)2 .56 3 .14 38 95 100 100 100 100 (60) (0) (0)2 .56 3 .14 23 58 100 100 100 100 (60) (0) (0)2 .56 3 .14 68 95 100 100 100 100 (28) (0) (0)2 .56 3 .14 10 92 100 100 100 100 (89) (0) (0)2 .56 3 .14 33 87 100 100 100 100 (62) (0) (0)2 .56 3 .14 13 90 95 100 100 95 (85) (5) (0)2 .56 3 .56 13 37 100 100 100 100 (64) (0) (0)2 .56 3 .56 15 58 100 100 100 100 (74) (0) (0)2 .56 3 .56 0 88 100 100 100 100 (100) (0) (0)2 .56 3 .56 0 77 100 100 100 100 (100) (0) (0)2 .56 3 .56 13 95 100 100 100 100 (86) (0) (0)2 .56 3 .56 20 87 100 100 100 100 (77) (0) (0)2 .56 3 .56 40 90 98 100 95 95 (55) (2) (0)2 .56 3 .56 15 95 100 100 100 100 (84) (0) (0)2 .56 3 .56 13 92 100 100 100 100 (85) (0) (0)2 .56 3 .56 28 87 100 100 100 100 (67) (0) (0)2 .56 3 2.24 5 77 100 100 100 100 (93) (0) (0)2 .56 3 2.24 43 95 98 100 95 100 (54) (2) (5)2 .56 3 2.24 8 90 95 100 95 95 (91) (5) (0)2 .56 3 2.24 0 87 98 100 100 100 (100) (2) (0)2 .56 3 2.24 8 92 100 100 100 100 (91) (0) (0)2 1.12 3 .03 40 65 100 100 100 100 (38) (0) (0)2 1.12 3 .03 70 95 100 100 100 100 (26) (0) (0)2 1.12 3 .04 23 87 100 100 100 100 (73) (0) (0)2 1.12 3 .07 40 72 100 98 100 100 (44) (0) (0)2 1.12 3 .07 43 95 100 100 100 100 (54) (0) (0)2 1.12 3 .14 90 65 98 100 98 100 (0) (2) (2)2 1.12 3 .14 8 90 100 100 100 100 (91) (0) (0)2 1.12 3 .14 50 95 100 100 100 100 (47) (0) (0)2 1.12 3 .14 43 95 100 100 100 100 (54) (0) (0)2 1.12 3 .14 28 87 100 100 100 100 (67) (0) (0)2 1.12 3 .14 15 72 100 98 100 100 (79) (0) (0)2 1.12 3 .14 25 95 100 100 100 100 (73) (0) (0)2 1.12 3 .14 55 93 100 100 100 100 (40) (0) (0)2 1.12 3 .14 33 98 100 100 98 100 (66) (0) (2)2 1.12 3 .14 65 100 100 100 100 100 (35) (0) (0)2 1.12 3 .56 60 65 100 100 100 100 (7) (0) (0)2 1.12 3 .56 15 87 100 100 100 100 (82) (0) (0)2 1.12 3 .56 15 72 100 98 100 100 (79) (0) (0)2 1.12 3 .56 70 95 100 100 100 100 (26) (0) (0)2 1.12 3 .56 20 90 100 100 100 100 (77) (0) (0)2 1.12 3 .56 15 95 100 100 100 100 (84) (0) (0)2 1.12 3 .56 23 98 100 100 100 100 (76) (0) (0)2 1.12 3 .56 38 93 100 100 95 100 (59) (0) (5)2 1.12 3 .56 75 100 100 100 100 100 (25) (0) (0)2 1.12 3 .56 15 95 100 100 98 100 (84) (0) (2)2 1.12 3 2.24 20 90 100 100 100 100 (77) (0) (0)2 1.12 3 2.24 28 100 100 100 100 100 (72) (0) (0)2 1.12 3 2.24 15 95 100 100 100 100 (84) (0) (0)2 1.12 3 2.24 35 93 100 100 100 100 (62) (0) (0)2 1.12 3 2.24 15 98 98 100 100 100 (84) (2) (0)2 2.24 3 .03 90 90 98 100 100 100 (0) (2) (0)2 2.24 3 .03 93 97 100 100 100 100 (4) (0) (0)2 2.24 3 .04 25 60 100 100 100 100 (58) (0) (0)2 2.24 3 .07 95 99 100 100 100 100 (4) (0) (0)2 2.24 3 .07 68 97 100 100 100 100 (29) (0) (0)2 2.24 3 .14 63 97 100 100 100 100 (35) (0) (0)2 2.24 3 .14 88 90 100 100 100 100 (2) (0) (0)2 2.24 3 .14 45 99 100 100 100 100 (54) (0) (0)2 2.24 3 .14 45 60 100 100 100 100 (25) (0) (0)2 2.24 3 .14 63 97 98 100 100 100 (35) (2) (0)2 2.24 3 .14 53 97 100 100 100 100 (45) (0) (0)2 2.24 3 .14 35 98 100 100 100 100 (64) (0) (0)2 2.24 3 .14 85 97 100 100 100 100 (12) (0) (0)2 2.24 3 .14 50 100 100 100 100 100 (50) (0) (0)2 2.24 3 .14 80 98 100 100 100 100 (18) (0) (0)2 2.24 3 .56 33 97 100 100 100 100 (65) (0) (0)2 2.24 3 .56 35 90 100 100 100 100 (61) (0) (0)2 2.24 3 .56 25 60 100 100 100 100 (58) (0) (0)2 2.24 3 .56 63 97 100 100 100 100 (35) (0) (0)2 2.24 3 .56 53 99 100 100 100 100 (46) (0) (0)2 2.24 3 .56 20 97 100 100 100 100 (79) (0) (0)2 2.24 3 .56 73 100 100 100 100 100 (27) (0) (0)2 2.24 3 .56 78 98 100 100 100 100 (20) (0) (0)2 2.24 3 .56 35 98 100 100 100 100 (64) (0) (0)2 2.24 3 .56 55 97 100 100 98 100 (43) (0) (2)2 2.24 3 2.24 20 97 100 100 100 100 (79) (0) (0)2 2.24 3 2.24 25 98 100 100 100 100 (74) (0) (0)2 2.24 3 2.24 55 100 100 100 100 100 (45) (0) (0)2 2.24 3 2.24 55 98 100 100 100 100 (43) (0) (0)2 2.24 3 2.24 80 97 100 100 100 100 (17) (0) (0)2 .56 4 .14 58 95 100 100 100 100 (38) (0) (0)2 .56 4 .14 33 90 100 100 98 95 (63) (0) (0)2 .56 4 .56 48 95 100 100 98 100 (49) (0) (2)2 .56 4 .56 20 90 100 100 98 95 (77) (0) (0)2 .56 4 2.24 20 95 98 100 100 100 (78) (2) (0)2 .56 4 2.24 28 90 100 100 95 95 (68) (0) (0)2 1.12 4 .14 60 100 100 100 100 100 (40) (0) (0)2 1.12 4 .14 33 93 98 100 98 100 (64) (2) (2)2 1.12 4 .56 63 100 100 100 100 100 (37) (0) (0)2 1.12 4 .56 30 93 100 100 100 100 (67) (0) (0)2 1.12 4 2.24 50 100 100 100 100 100 (50) (0) (0)2 1.12 4 2.24 63 93 100 100 100 100 (32) (0) (0)2 2.24 4 .14 70 100 100 100 100 100 (30) (0) (0)2 2.24 4 .14 53 97 100 100 100 100 (45) (0) (0)2 2.24 4 .56 53 97 100 100 100 100 (45) (0) (0)2 2.24 4 .56 65 100 100 100 100 100 (35) (0) (0)2 2.24 4 2.24 50 97 100 100 100 100 (48) (0) (0)2 2.24 4 2.24 50 100 100 100 100 100 (50) (0) (0)2 .56 5 .14 35 95 100 100 100 100 (63) (0) (0)2 .56 5 .14 78 90 100 100 90 95 (13) (0) (5)2 .56 5 .56 38 90 100 100 100 95 (57) (0) (0)2 .56 5 .56 40 95 100 100 95 100 (57) (0) (5)2 .56 5 2.24 23 95 100 100 100 100 (75) (0) (0)2 .56 5 2.24 5 90 100 100 98 95 (94) (0) (0)2 1.12 5 .14 58 100 100 100 100 100 (42) (0) (0)2 1.12 5 .14 38 93 100 100 95 100 (59) (0) (5)2 1.12 5 .56 35 93 100 100 100 100 (62) (0) (0)2 1.12 5 .56 53 100 100 100 100 100 (47) (0) (0)2 1.12 5 2.24 23 100 100 100 100 100 (77) (0) (0)2 1.12 5 2.24 28 93 100 100 100 100 (69) (0) (0)2 2.24 5 .14 73 97 100 100 100 100 (24) (0) (0)2 2.24 5 .14 85 100 100 100 100 100 (15) (0) (0)2 2.24 5 .56 73 97 100 100 100 100 (24) (0) (0)2 2.24 5 .56 73 100 100 100 100 100 (27) (0) (0)2 2.24 5 2.24 68 100 100 100 100 100 (32) (0) (0)2 2.24 5 2.24 90 97 100 100 100 100 (7) (0) (0)2 .56 13 .14 78 90 100 100 100 95 (13) (0) (0)2 .56 13 .56 70 90 100 100 100 95 (22) (0) (0)2 .56 13 2.24 40 90 98 100 95 95 (55) (2) (0)2 1.12 13 .14 93 93 100 100 98 100 (0) (0) (2)2 1.12 13 .56 65 93 100 100 100 100 (30) (0) (0)2 1.12 13 2.24 28 93 100 100 100 100 (69) (0) (0)2 2.24 13 .14 98 97 100 100 100 100 (0) (0) (0)2 2.24 13 .56 85 97 100 100 100 100 (12) (0) (0)2 2.24 13 2.24 83 97 100 100 100 100 (14) (0) (0)2 .56 6 .14 63 90 100 100 90 95 (30) (0) (5)2 .56 6 .14 30 95 100 100 100 100 (68) (0) (0)2 .56 6 .56 55 95 100 100 100 100 (42) (0) (0)2 .56 6 .56 40 90 100 100 100 95 (55) (0) (0)2 .56 6 2.24 18 90 100 100 98 95 (80) (0) (0)2 .56 6 2.24 60 95 100 100 100 100 (36) (0) (0)2 1.12 6 .14 63 93 100 100 100 100 (32) (0) (0)2 1.12 6 .14 50 100 100 100 100 100 (50) (0) (0)2 1.12 6 .56 55 100 100 100 100 100 (45) (0) (0)2 1.12 6 .56 20 93 100 100 100 100 (78) (0) (0)2 1.12 6 2.24 58 93 100 100 98 100 (37) (0) (2)2 1.12 6 2.24 28 100 100 100 100 100 (72) (0) (0)2 2.24 6 .14 73 100 100 100 100 100 (27) (0) (0)2 2.24 6 .14 60 97 100 100 100 100 (38) (0) (0)2 2.24 6 .56 80 100 100 100 100 100 (20) (0) (0)2 2.24 6 .56 40 97 100 100 100 100 (58) (0) (0)2 2.24 6 2.24 45 97 100 100 100 100 (53) (0) (0)2 2.24 6 2.24 60 100 100 100 100 100 (40) (0) (0)2 .56 27 .14 78 92 100 100 100 100 (15) (0) (0)2 .56 27 .56 30 92 100 100 100 100 (67) (0) (0)2 .56 27 2.24 18 92 100 100 100 100 (80) (0) (0)2 1.12 27 .14 88 95 100 100 100 100 (7) (0) (0)2 1.12 27 .56 55 95 100 100 100 100 (42) (0) (0)2 1.12 27 2.24 10 95 100 100 98 100 (89) (0) (2)2 2.24 27 .14 88 98 100 100 100 100 (10) (0) (0)2 2.24 27 .56 83 98 100 100 100 100 (15) (0) (0)2 2.24 27 2.24 50 98 100 100 100 100 (48) (0) (0)2 .56 7 .14 10 92 100 100 100 100 (89) (0) (0)2 .56 7 .56 13 92 98 100 100 100 (85) (2) (0)2 .56 7 2.24 10 92 100 100 100 100 (89) (0) (0)2 1.12 7 .14 33 95 100 100 100 100 (65) (0) (0)2 1.12 7 .56 30 95 100 100 100 100 (68) (0) (0)2 1.12 7 2.24 15 95 100 100 98 100 (84) (0) (2)2 2.24 7 .14 83 98 100 100 100 100 (15) (0) (0)2 2.24 7 .56 20 98 100 100 100 100 (79) (0) (0)2 2.24 7 2.24 20 98 100 100 100 100 (79) (0) (0)2 .56 8 .14 20 92 100 100 95 100 (78) (0) (5)2 .56 8 .56 13 92 100 100 98 100 (85) (0) (2)2 .56 8 2.24 5 92 100 100 100 100 (94) (0) (0)2 1.12 8 .14 5 95 100 100 100 100 (94) (0) (0)2 1.12 8 .56 28 95 100 100 100 100 (70) (0) (0)2 1.12 8 2.24 60 95 100 100 100 100 (36) (0) (0)2 2.24 8 .14 33 98 100 100 100 100 (66) (0) (0)2 2.24 8 .56 20 89 100 100 100 100 (79) (0) (0)2 2.24 8 2.24 25 98 98 100 100 100 (74) (2) (0)2 .56 9 .07 23 58 100 100 100 100 (60) (0) (0)2 .56 9 .14 38 58 100 100 100 100 (34) (0) (0)2 .56 9 .14 0 77 100 100 100 100 (100) (0) (0)2 .56 9 .56 15 58 100 100 100 100 (74) (0) (0)2 .56 9 .56 10 77 100 100 100 100 (87) (0) (0)2 .56 9 2.24 10 77 100 100 100 100 (87) (0) (0)2 1.12 9 .07 30 72 100 98 100 100 (58) (0) (0)2 1.12 9 .14 13 90 100 100 100 100 (85) (0) (0)2 1.12 9 .14 18 72 100 98 100 100 (75) (0) (0)2 1.12 9 .56 15 90 100 100 100 100 (83) (0) (0)2 1.12 9 .56 25 72 100 98 100 100 (65) (0) (0)2 1.12 9 2.24 5 90 100 100 100 100 (94) (0) (0)2 2.24 9 .07 63 97 100 100 100 100 (35) (0) (0)2 2.24 9 .14 53 97 100 100 100 100 (45) (0) (0)2 2.24 9 .14 25 97 100 100 100 100 (74) (0) (0)2 2.24 9 .56 25 97 100 100 100 100 (74) (0) (0)2 2.24 9 .56 33 97 100 100 100 100 (65) (0) (0)2 2.24 9 2.24 5 97 100 100 100 100 (94) (0) (0)2 .56 20 .03 25 87 100 100 100 100 (71) (0) (0)2 .56 20 .04 23 88 95 100 100 100 (73) (5) (0)2 .56 20 .07 5 58 100 100 100 100 (91) (0) (0)2 .56 20 .07 23 95 100 100 100 100 (75) (0) (0)2 .56 20 .14 23 95 95 100 100 100 (75) (5) (0)2 .56 20 .14 5 77 100 100 100 100 (93) (0) (0)2 .56 20 .14 35 58 100 100 100 100 (39) (0) (0)2 .56 20 .14 15 87 100 100 100 100 (82) (0) (0)2 .56 20 .14 8 88 100 100 100 100 (90) (0) (0)2 .56 20 .56 10 88 98 100 100 100 (88) (2) (0)2 .56 20 .56 5 77 100 100 100 100 (93) (0) (0)2 .56 20 .56 0 95 98 100 100 100 (100) (2) (0)2 .56 20 .56 10 87 100 100 100 100 (88) (0) (0)2 .56 20 .56 0 58 100 100 100 100 (100) (0) (0)2 .56 20 2.24 15 77 100 100 100 100 (80 (0) (0)2 1.12 20 .03 63 95 100 100 100 100 (33) (0) (0)2 1.12 20 .04 40 87 100 100 100 100 (54) (0) (0)2 1.12 20 .07 20 72 100 98 100 100 (72) (0) (0)2 1.12 20 .07 53 95 100 100 100 100 (44) (0) (0)2 1.12 20 .14 10 87 100 100 100 100 (88) (0) (0)2 1.12 20 .14 8 72 100 98 100 100 (88) (0) (0)2 1.12 20 .14 40 95 95 100 100 100 (57) (5) (0)2 1.12 20 .14 38 95 100 100 100 100 (60) (0) (0)2 1.12 20 .14 0 90 100 100 100 100 (100) (0) (0)2 1.12 20 .56 0 87 98 100 100 100 (100) (2) (0)2 1.12 20 .56 5 95 100 100 100 100 (94) (0) (0)2 1.12 20 .56 28 95 100 100 100 100 (70) (0) (0)2 1.12 20 .56 25 72 100 98 100 100 (65) (0) (0)2 1.12 20 .56 15 90 100 100 100 100 (83) (0) (0)2 1.12 20 2.24 13 90 100 100 100 100 (85) (0) (0)2 2.24 20 .03 65 97 100 100 100 100 (32) (0) (0)2 2.24 20 .04 43 60 100 100 98 100 (28) (0) (2)2 2.24 20 .07 30 97 100 100 100 100 (69) (0) (0)2 2.24 20 .07 83 99 100 100 100 100 (16) (0) (0)2 2.24 20 .14 25 97 100 100 100 100 (74) (0) (0)2 2.24 20 .14 18 97 100 100 100 100 (81) (0) (0)2 2.24 20 .14 58 97 100 100 100 100 (40) (0) (0)2 2.24 20 .14 38 99 100 100 100 100 (61) (0) (0)2 2.24 20 .14 35 60 100 100 100 100 (41) (0) (0)2 2.24 20 .56 18 97 100 100 100 100 (81) (0) (0)2 2.24 20 .56 25 99 100 100 100 100 (74) (0) (0)2 2.24 20 .56 25 60 100 100 100 100 (58) (0) (0)2 2.24 20 .56 53 97 100 100 100 100 (45) (0) (0)2 2.24 20 .56 28 97 100 100 100 100 (71) (0) (0)2 2.24 20 2.24 25 97 100 100 100 100 (74) (0) (0)2 .56 12 .03 28 87 100 100 100 100 (67) (0) (0)2 .56 12 .07 13 95 100 100 100 100 (86) (0) (0)2 .56 12 .14 17 87 100 100 100 100 (80) (0) (0)2 .56 12 .14 20 95 98 100 100 100 (78) (2) (0)2 .56 12 .56 5 87 100 100 100 100 (94) (0) (0)2 .56 12 .56 10 95 98 100 100 100 (89) (2) (0)2 1.12 12 .03 88 95 100 100 100 100 (7) (0) (0)2 1.12 12 .07 53 95 100 100 100 100 (44) (0) (0)2 1.12 12 .14 33 95 100 100 100 100 (65) (0) (0)2 1.12 12 .14 28 95 100 100 100 100 (70) (0) (0)2 1.12 12 .56 20 95 100 100 100 100 (78) (0) (0)2 1.12 12 .56 18 95 100 100 100 100 (81) (0) (0)2 2.24 12 .03 98 97 100 100 100 100 (0) (0) (0)2 2.24 12 .07 75 99 100 100 100 100 (24) (0) (0)2 2.24 12 .14 85 99 100 100 100 100 (14) (0) (0)2 2.24 12 .14 88 97 100 100 100 100 (9) (0) (0)2 2.24 12 .56 60 97 100 100 100 100 (38) (0) (0)2 2.24 12 .56 23 99 100 100 100 100 (76) (0) (0)2 .56 24 .03 18 37 100 100 100 100 (51) (0) (0)2 .56 24 .04 5 88 95 100 100 100 (94) (5) (0)2 .56 24 .14 15 88 95 100 100 100 (82) (5) (0)2 .56 24 .14 0 37 98 100 98 100 (100) (2) (2)2 .56 24 .56 0 37 98 100 98 100 (100) (2) (2)2 .56 24 .56 5 88 100 100 100 100 (94) (0) (0)2 1.12 24 .03 25 65 100 100 100 100 (61) (0) (0)2 1.12 24 .04 25 87 100 100 100 100 (71) (0) (0)2 1.12 24 .14 8 65 100 100 98 100 (87) (0) (2)2 1.12 24 .14 10 87 100 100 100 100 (88) (0) (0)2 1.12 24 .56 30 87 100 100 100 100 (65) (0) (0)2 1.12 24 .56 20 65 98 100 100 100 (69) (2) (0)2 2.24 24 .03 23 90 100 100 100 100 (74) (0) (0)2 2.24 24 .04 50 60 100 100 100 100 (16) (0) (0)2 2.24 24 .14 10 60 100 100 100 100 (83) (0) (0)2 2.24 24 .14 55 90 98 100 100 100 (38) (2) (0)2 2.24 24 .56 8 60 100 100 100 100 (86) (0) (0)2 2.24 24 .56 28 90 100 100 100 100 (68) (0) (0)2 .56 26 .04 18 88 100 100 100 100 (79) (0) (0)2 .56 26 .14 0 88 100 100 100 100 (100) (0) (0)2 .56 26 .56 15 88 98 100 100 100 (82) (2) (0)2 1.12 26 .04 20 87 100 100 98 100 (77) (0) (2)2 1.12 26 .14 8 87 100 100 100 100 (90) (0) (0)2 1.12 26 .56 13 87 98 100 100 100 (85) (2) (0)2 2.24 26 .04 45 60 100 100 100 100 (25) (0) (0)2 2.24 26 .14 25 60 100 100 100 100 (58) (0) (0)2 2.24 26 .56 8 60 100 100 100 100 (86) (0) (0)2 .56 23 .04 18 88 98 100 10 100 (79) (2) (0)2 .56 23 .14 10 88 100 100 100 100 (88) (0) (0)2 .56 23 .56 5 88 98 100 98 100 (94) (2) (0)2 1.12 23 .04 20 87 98 100 100 100 (77) (2) (0)2 1.12 23 .14 13 87 100 100 98 100 (85) (0) (2)2 1.12 23 .56 23 87 100 100 100 100 (73) (0) (0)2 2.24 23 .04 58 60 100 100 100 100 (3) (0) (0)2 2.24 23 .14 40 60 100 100 10 100 (33) (0) (0)2 2.24 23 .56 30 60 100 100 100 100 (50) (0) (0)13 4.48 2 .14 100 100 100 100 8 63 (0) (0) (87)13 4.48 2 .56 10 100 100 100 15 63 (0) (0) (76)13 4.48 2 2.24 100 100 100 100 5 63 (0) (0) (92)13 6.72 2 .14 100 100 100 100 50 88 (0) (0) (43)13 6.72 2 .56 100 100 100 100 28 88 (0) (0) (68)13 6.72 2 2.24 100 100 100 100 25 88 (0) (0) (71)13 8.96 2 .14 100 100 10 100 15 90 (0) (0) (83)13 8.96 2 .56 100 100 100 10 13 90 (0) (0) (85)13 8.96 2 2.24 100 100 100 100 15 90 (0) (0) (83)13 4.48 3 .14 100 100 100 100 8 63 (0) (0) (87)13 4.48 3 .14 100 100 0 53 (0) (100)13 4.48 3 .56 10 100 0 53 (0) (100)13 4.48 3 .56 10 100 100 100 5 63 (0) (0) (92)13 4.48 3 2.24 100 100 5 53 (0) (90)13 4.48 3 2.24 100 100 100 100 5 63 (0) (0) (92)13 6.72 3 .14 100 100 100 100 23 88 (0) (0) (73)13 6.72 3 .14 100 100 5 70 (0) (92)13 6.72 3 .56 100 100 5 70 (0) (92)13 6.72 3 .56 100 100 100 100 20 88 (0) (0) (77)13 6.72 3 2.24 100 100 100 100 23 88 (0) (0) (73)13 6.72 3 2.24 100 100 5 70 (0) (92)13 8.96 3 .14 100 100 10 85 (0) (88)13 8.96 3 .14 100 100 100 100 13 90 (0) (0) (85)13 8.96 3 .56 100 100 0 85 (0) (100)13 8.96 3 .56 100 100 100 100 13 90 (0) (0) (85)13 8.96 3 2.24 10 100 100 100 8 90 (0) (0) (91)13 8.96 3 2.24 100 100 0 85 (0) (100)13 4.48 20 .14 100 100 100 100 10 63 (0) (0) (84)13 4.48 20 .14 100 100 5 53 (0) (90)13 4.48 20 .56 100 100 0 53 (0) (100)13 4.48 20 .56 100 100 10 100 28 63 (0) (0) (55)13 4.48 20 2.24 10 100 0 53 (0) (100)13 4.48 20 2.24 100 100 100 100 18 63 (0) (0) (71)13 6.72 20 .14 100 100 0 70 (0) (100)13 6.72 20 .14 100 100 100 100 25 88 (0) (0) (71)13 6.72 20 .56 100 100 100 100 35 88 (0) (0) (60)13 6.72 20 .56 100 100 0 70 (0) (100)13 6.72 20 2.24 100 100 0 70 (0) (100)13 6.72 20 2.24 10 100 100 100 23 88 (0) (0) (73)13 8.96 20 .14 100 100 100 100 35 90 (0) (0) (61)13 8.96 20 .14 100 100 5 85 (0) (94)13 8.96 20 .56 100 100 0 85 (0) (100)13 8.96 20 .56 10 100 10 100 28 90 (0) (0) (68)13 8.96 20 2.24 10 100 0 85 (0) (100)13 8.96 20 2.24 100 100 10 100 30 90 (0) (0) (66)13 4.48 24 .14 100 100 5 53 (0) (90)13 4.48 24 .56 100 100 5 53 (0) (90)13 4.48 24 2.24 10 100 0 53 (0) (100)13 6.72 24 .14 100 100 10 70 (0) (85)13 6.72 24 .56 100 100 5 70 (0) (92)13 6.72 24 2.24 100 100 10 70 (0) (85)13 8.96 24 .14 100 100 13 85 (0) (84)13 8.96 24 .56 100 100 5 85 (0) (94)13 8.96 24 2.24 100 100 5 85 (0) (94)4 1.12 1 .14 98 100 98 100 0 80 (2) (2) (100)4 1.12 1 .56 100 100 100 100 10 80 (0) (0) (87)4 1.12 1 2.24 100 100 100 100 0 80 (0) (0) (100)4 2.24 1 .14 100 100 100 98 5 87 (0) (0) (94)4 2.24 1 .56 100 100 100 98 0 87 (0) (0) (100)4 2.24 1 2.24 100 100 100 98 0 87 (0) (0) (100)4 4.48 1 .14 100 100 100 100 23 100 (0) (0) (77)4 4.48 1 .56 100 100 100 100 0 100 (0) (0) (100)4 4.48 1 2.24 100 100 100 100 0 100 (0) (0) (100)4 1.12 2 .14 100 98 98 98 0 15 (0) (0) (100)4 1.12 2 .14 100 100 100 100 0 80 (0) (0) (100)4 1.12 2 .56 100 100 100 100 0 80 (0) (0) (100)4 1.12 2 .56 100 98 95 98 18 15 (0) (3) (0)4 1.12 2 2.24 100 98 100 98 8 15 (0) (0) (46)4 1.12 2 2.24 100 100 10 100 0 80 (0) (0) (100)4 2.24 2 .14 100 100 100 100 0 48 (0) (0) (100)4 2.24 2 .14 100 10 100 98 0 87 (0) (0) (100)4 2.24 2 .56 100 100 95 100 0 48 (0) (5) (100)4 2.24 2 .56 100 100 100 98 0 87 (0) (0) (100)4 2.24 2 2.24 100 100 98 100 0 48 (0) (2) (100)4 2.24 2 2.24 100 100 100 98 18 87 (0) (0) (79)4 4.48 2 .14 100 100 100 100 0 92 (0) (0) (100)4 4.48 2 .14 100 100 100 100 13 100 (0) (0) (87)4 4.48 2 .56 100 100 98 100 0 92 (0) (2) (100)4 4.48 2 .56 100 100 100 100 8 100 (0) (0) (92)4 4.48 2 2.24 100 100 100 100 0 92 (0) (0) (100)4 4.48 2 2.24 10 100 100 100 5 100 (0) (0) (95)4 1.12 3 .14 100 100 100 100 8 80 (0) (0) (90)4 1.12 3 .56 98 100 100 100 5 80 (2) (0) (93)4 1.12 3 2.24 98 100 100 100 0 80 (2) (0) (100)4 2.24 3 .14 100 100 100 98 20 87 (0) (0) (77)4 2.24 3 .56 100 100 10 98 5 87 (0) (0) (94)4 2.24 3 2.24 100 100 100 98 0 87 (0) (0) (100)4 4.48 3 .14 100 100 100 100 5 100 (0) (0) (95)4 4.48 3 .56 100 100 100 100 0 100 (0) (0) (100)4 4.48 3 2.24 100 100 100 100 5 100 (0) (0) (95)4 1.12 4 .14 100 100 100 100 0 90 (0) (0) (100)4 1.12 4 .14 100 100 100 100 0 80 (0) (0) (100)4 1.12 4 .56 100 100 100 100 0 90 (0) (0) (100)4 1.12 4 .56 100 100 100 100 10 80 (0) (0) (87)4 1.12 4 2.24 100 100 100 100 0 80 (0) (0) (100)4 1.12 4 2.24 100 100 100 100 0 90 (0) (0) (100)4 2.24 4 .14 100 100 100 100 5 85 (0) (0) (94)4 2.24 4 .14 100 100 100 98 0 87 (0) (0) (100)4 2.24 4 .56 100 100 100 98 5 87 (0) (0) (94)4 2.24 4 .56 100 100 100 100 0 85 (0) (0) (100)4 2.24 4 2.24 100 100 100 100 8 85 (0) (0) (90)4 2.24 4 2.24 100 100 100 98 5 87 (0) (0) (94)4 4.48 4 .14 100 100 100 100 0 100 (0) (0) (100)4 4.48 4 .14 100 100 100 100 13 98 (0) (0) (86)4 4.48 4 .56 100 100 100 100 5 100 (0) (0) (95)4 4.48 4 .56 100 100 100 100 13 98 (0) (0) (86)4 4.48 4 2.24 100 100 100 100 10 100 (0) (0) (90)4 4.48 4 2.24 100 100 10 100 25 98 (0) (0) (74)4 1.12 5 .14 100 100 100 100 5 80 (0) (0) (93)4 1.12 5 .56 100 100 100 100 8 80 (0) (0) (90)4 1.12 5 2.24 100 100 100 100 0 80 (0) (0) (100)4 2.24 5 .56 100 100 10 98 0 87 (0) (0) (100)4 2.24 5 2.24 100 100 100 98 0 87 (0) (0) (100)4 4.48 5 .14 100 100 100 100 68 100 (0) (0) (32)4 4.48 5 .56 100 100 100 100 8 100 (0) (0) (92)4 4.48 5 2.24 100 100 100 100 5 100 (0) (0) (95)4 1.12 13 .14 100 100 100 100 15 80 (0) (0) (81)4 1.12 13 .56 100 100 100 100 0 80 (0) (0) (100)4 1.12 13 2.24 100 100 100 100 0 80 (0) (0) (100)4 2.24 13 .14 100 100 100 98 53 87 (0) (0) (39)4 2.24 13 .56 10 100 100 98 35 87 (0) (0) (59)4 2.24 13 2.24 100 100 100 98 8 87 (0) (0) (90)4 4.48 13 .14 100 100 10 100 95 100 (0) (0) (5)4 4.48 13 .56 100 100 100 100 75 100 (0) (0) (25)4 4.48 13 2.24 100 100 100 100 28 100 (0) (0) (72)4 1.12 6 .14 95 100 100 100 0 80 (5) (0) (100)4 1.12 6 .56 98 100 98 100 5 80 (2) (2) (93)4 1.12 6 2.24 100 100 100 100 0 80 (0) (0) (100)4 2.24 6 .14 100 100 100 98 0 87 (0) (0) (100)4 2.24 6 .56 100 100 100 98 0 87 (0) (0) (100)4 2.24 6 2.24 10 100 100 98 0 87 (0) (0) (100)4 4.48 6 .14 100 100 10 100 23 100 (0) (0) (77)4 4.48 6 .56 100 100 100 100 5 100 (0) (0) (95)4 4.48 6 2.24 100 100 10 100 0 100 (0) (0) (100)__________________________________________________________________________
EXAMPLE 42
The following procedure was used to determine the interaction between a herbicide and antidote when the herbicide is topically applied to the soil surface and the antidote is applied to crop seed. Crop plant seed was treated with the antidote either by contacting the seed with antidote in powder form or by contacting the seed with a solution or suspension of antidote compound dissolved or suspended in a suitable solvent, typically methylene chloride or toluene. Relative amounts of antidote compound and seed were used to provide an antidote-on-seed concentration, on a percent weight/weight basis. Containers were filled and compacted with fumigated silt loam type soil to a depth of about 1.3 cm from the top of the container. A first container was designated as an untreated control, a second container was designated as an untreated control, a and a third container was designated as a herbicide+antidote test container. Untreated crop seed was placed in the first and second containers. Antidote-treated crop seed was placed in the third container. Then, each of the second and third containers was filled and leveled with a cover layer of soil having incorporated therein the selected herbicide at a pre-determined concentration. The first container was filled and leveled with soil containing no herbicide. All containers were given about 0.6 cm of overhead water to simulate an activating rainfall. The containers were placed on a greenhouse bench and sub-irrigated as required for the duration of the test. Plant response was observed about three weeks after initial treatment. Results are set forth in Table 5. Herbicide rate is given in kg/ha and antidote rate is given in percent weight/weight of antidote/seed.
TABLE 5______________________________________% PLANT INHIBITION AND % SAFENING EFFECT ( ) ANTI- Sorghum FoxtailHERB. DOTE Grain GreenNO. RATE NO. RATE W WO W WO______________________________________2 .56 3 .03 0 22 98 100 (100) (2)2 .56 3 .06 0 22 98 100 (100) (2)2 .56 3 .13 15 22 95 100 (31) (5)2 1.12 3 .03 5 50 98 100 (90) (2)2 1.12 3 .06 0 50 100 100 (100) (0)2 1.12 3 .13 5 50 100 100 (90) (0)2 2.24 3 .03 5 65 98 100 (92) (2)2 2.24 3 .06 15 65 100 100 (76) (0)2 2.24 3 .13 5 65 100 100 (92) (0)2 .56 20 .03 0 22 98 100 (100) (2)2 .56 20 .06 5 22 100 100 (77) (0)2 .56 20 .13 0 22 100 100 (100) (0)2 1.12 20 .03 8 50 100 100 (84) (0)2 1.12 20 .06 0 50 100 100 (100) (0)2 1.12 20 .13 5 50 100 100 (90) (0)2 2.24 20 .03 0 65 100 100 (100) (0)2 2.24 20 .06 10 65 100 100 (84) (0)2 2.24 20 .13 10 65 100 100 (84) (0)______________________________________
Following the same procedures described above in Examples 40 to 42, additional tests were conducted in order to exemplify the safening, antidotal properties of the compounds of Examples 33-38 with a plurality of herbicides from diverse classes of chemicals including some of those in the above list of Herbicide Nos. 1-14 previously tested with the safener compounds of Examples 1-32 (see Tables 2-5). Additional herbicides include the following compounds:
______________________________________Herb No. Name______________________________________15 2-Methoxy-3,6-dichlorobenzoic acid, dimethylamine salt.16 As-triazine-5(4H)one,4-amino-, 6-tert-butyl-,3-(methylthio)-;17 4-Chloro-5-(methylamino)-2- (alpha, alpha, alpha-trifluoro- m-tolyl)-3(2H)-pyridazonone;18 Benzeneamine, N-(1-ethylpropyl)-3, 4-dimethyl-2,6-dinitro-19 Benzenesulfonamide, 2-chloro-N- [[(4-methoxy-6-methyl-1,3,5- triazin-2-yl)amino]carbonyl]-;20 Benzoic acid, 2-[[[[(4,6-dimethyl- 2-pyrimidinyl)amino]carbonyl]amino] sulfonyl]-, methyl ester;21 Benzoic acid, 2-[[[[[(4,6-dimethyloxy- 2-pyrimidinyl)amino]carbonyl]amino] sulfonyl]methyl]-, methyl ester;22 3-Quinolinecarboxylic acid, 2-[4, 5-dihydro-4-methyl-4-(1-methyl- ethyl)-5-oxo-1h-imidazol-2-YL]-;23 3-isoxazolidinone, 2-[(2-chlorophenyl)methyl]-4,4- dimethyl-24 3-Pyridinecarboxylic acid, 2- (difluoromethyl)-5-(4,5-dihydro- 2-thiazolyl)-4-(2-methylpropyl)-6- (trifluoromethyl)-, methyl ester;25 3-Pyridinecarboxylic acid, 2-[4,5- dihydro-4-methyl-4-(1-methylethyl)- 5-oxo-1H-imidazol-2-yl]-;26 Benzoic acid, 2-[[[[(4-methoxy-6- methyl-1,3,5-triazin-2-YL)amino] carbonyl]amino]sulfonyl]-, methyl ester;27 3-Pyridinecarboxylic acid, 5-ethyl- 2--[4-methyl-4-(1-methylethyl)-5- oxo-1H-imidazol-2-yl]-;28 Benzoic acid, 2-[[[[(4-chloro-6- methoxy-2-pyrimidinyl)amino]- carbonyl]amino]sulfonyl]-, ethyl ester;29 Benzenesulfonamide, 2-(2-chloroethoxy)- N-[[(4-methoxy-6-methyl-1,3,5- triazin-2-yl)amino]carbonyl]-;30 2-Thiophenecarboxylic acid, 3-[[[[ (4,6-dimethoxy-1,3,5-triazin-2-yl)- amino]carbonyl]amino]sulfonyl]-, methyl ester;31 3-Pyridinecarboxylic acid, 2-]4,5- dihydro-4-methyl-4-(1methylethyl)- 5-oxo-1H-imidazol-2-yl]-5-methyl-, ammonium salt;32 Benzoic acid, 2-[4,5-dihydro-4- methyl-4-(1-methylethyl)-5-oxo-1H- imidazol-2-yl]-4(OR 5)-methyl-;33 2-Imidazolidinone, 3-[5-(1,1- dimethylethyl)-3-isoxazolyl]-4- hydroxy-1-methyl-;______________________________________
EXAMPLE 43
Following the test procedure described in Example 40, the antidotal properties of compounds listed in Table 1, mostly Antidote Nos. 33-38, were tested in combinations with a wide variety of herbicidal compounds, particularly Herbicide Nos. 15-33. Results are shown in Table 6.
TABLE 6 % PLANT INHIBITION AND % SAFENING EFFECT ( ) ANTI- Barnyard Sorghum Foxtail Pigweed Velvet Hemp Indian Tartary HERB. DOTE Corn Grass (Grain) Green Redroot Leaf Soybean Wheat Rice Sesbania Mustard Buckwheat N O. RATE NO. RATE W WO W WO W WO W WO W WO W WO W WO W WO W WO W WO W WO W WO 6 8.96 1 0.14 5 13 95 95 (62) (0) 6 11.20 1 0.14 0 30 95 95 ( 100) (0) 6 8.96 1 0.56 5 13 90 95 (62) (6) 6 11.20 1 0.56 0 30 90 9 5 (100) (6) 6 8.96 1 2.24 5 13 85 95 (62) (11) 6 11.20 1 2.24 0 30 85 95 (100) (11) 2 0.56 1 0.03 75 98 95 100 ( 24) (5) 2 2.24 1 0.03 98 98 100 100 (0) (0) 2 0.56 1 0.1490 98 100 100 (9) (0) 2 2.24 1 0.14 83 98 100 100(16) (0) 2 0.56 1 0.56 70 98 100 100 (29) (0) 2 2.24 1 0.56 85 98 100 100 (14) (0) 15 1.12 1 0.56 0 10 25 90 (100) (73) 15 1.12 1 0.56 10 10 60 50 (0) 15 4.48 1 0.56 35 35 100 50 (0) 15 4.48 1 0.56 60 75 85 100 (20) (15) 15 1.12 1 2.24 5 10 65 50 (50) 15 1.12 1 2.24 10 10 95 90 (0) 15 4.48 1 2.24 15 35 95 50 (58) 15 4.48 1 2.24 40 75 100 100 (47) (0) 15 1.12 1 8.96 0 10 90 90 (100) (0) 15 1.12 1 8.96 0 1035 50 (100) (30) 15 4.48 1 8.96 45 75 100 100(40) (0) 15 4.48 1 8.96 5 35 60 50 (86) 7 0.14 1 0.56 80 90 80 90 (12) (12) 7 0.56 1 0.56 100 100 100 100 (0) (0) 7 1.12 1 0.56 85 72 100 100 (0) 7 4.48 1 0.56 100 95 100 100 (0) 7 0.14 1 2.24 45 90 95 90 (50) 7 0.56 1 2.24 100 100 100 100 (0) (0) 7 1.12 1 2.24 80 72 100 100 (0) 7 4.48 1 2.24 95 95 100 100 (0) (0) 7 0.14 1 8.96 80 90 100 90 (12) 7 0.56 1 8.96 100 100 100 100 (0) (0) 7 1.12 1 8.96 85 72 100 100 (0) 7 4.48 1 8.96 100 95 100 1 00 (0) 16 0.56 1 0.56 35 10 40 100 90 (75) 16 2.24 1 0.56 0 20 90 95 100 100 (100) (6) (0) 16 0.56 1 2.24 0 45 40 100 90 16 2.24 1 2.24 35 20 100 95 100 100 (0) 16 0.56 1 8.96 5 20 40 100 90 (50) 16 2.24 1 8.96 20 20 90 95 100 100 (0) (6) (0) 17 1.68 1 0.14 90 88 100 100 (0) 17 3.36 1 0.14 80 95 100 100 (16) (0) 17 1.68 1 0.56 90 88 100 100 (0) 17 3.36 1 0.56 88 95 100 100 (8) (0) 17 1.68 1 2.24 85 88 100 100 (4) (0) 17 3.36 1 2.24 83 95 100 100 (13) (0) 18 0.56 1 0.56 95 78 0 97 (100) 18 1.12 1 0.56 55 42 100 100 (0) 18 2.24 1 0.56 95 97 100 100 (3) (0) 18 4.48 1 0.56 65 80 100 100 (19) (0) 18 0.56 1 2.24 65 78 95 97 (17) (3) 18 1.12 1 2.24 40 42 100 100 (5) (0) 18 2.24 1 2.24 100 97 100 100 (0) 18 4.48 1 2.24 70 80 100 100 (13) (0) 18 0.56 1 8.96 70 78 100 9 7 (11) 18 1.12 1 8.96 60 42 100 100 (0) 18 2.24 1 8.96 95 97 100 100 (3) (0) 18 4.48 1 8.96 90 80 100 100 (0) 19 0.009 1 1.12 90 90 95 88 (0) 19 0.01 1 1.12 25 90 90 85 (73) 19 0.03 1 1.12 10 30 95 95 (67) (0) 19 0.03 1 1.12 90 90 95 95 (0) (0) 19 0.07 1 1.12 45 97 90 90 (54) (0) 19 0.14 1 1.1265 70 95 95 (8) (0) 19 0.009 1 4.48 90 90 95 8 8 (0) 19 0.01 1 4.48 5 90 70 85 (95) (18) 19 0.03 1 4.48 90 90 95 95 (0) (0) 19 0.03 1 4.48 0 30 100 95 (100) 19 0.07 1 4.48 80 97 95 90 (18) 19 0.14 1 4.48 10 70 95 95 (86) (0) 20 0.004 1 1.12 15 22 0 25 0 10 (32) (100) (100) 20 0.004 1 1.12 70 30 30 27 20 0.004 1 1.12 0 12 0 10 (100) (100) 20 0.009 1 1.12 45 38 50 40 20 0.009 1 1.12 35 73 75 35 25 68 (53) (64) 20 0.009 1 1.12 80 60 25 42 (41) 20 0.004 1 4.48 0 12 60 10(100) 20 0.004 1 4.48 10 22 85 25 10 10 (55)(0) 20 0.004 1 4.48 70 30 20 27 (26) 20 0.009 1 4.48 65 73 90 35 60 68 (11) (12) 20 0.009 1 4.48 75 60 60 42 20 0.009 1 4.48 0 38 50 40 ( 100) 21 0.28 1 0.14 35 47 45 35 (26) 21 0.56 1 0.14 75 68 35 30 21 1.12 1 0.14 45 67 45 30 (33) 21 0.28 1 0.56 0 47 30 35 (100) (15) 21 0.56 1 0.5635 68 45 30 (49) 21 1.12 1 0.56 70 67 35 30 21 0.28 1 2.24 0 47 15 35 (100) (58) 21 0.56 1 2.24 45 68 35 30 (34) 21 1.12 1 2.24 25 67 25 30 (63) (17) 21 0.28 1 8.96 10 47 20 35(79) (43) 21 0.56 1 8.96 10 68 50 30 (86) 21 1.12 1 8.96 55 67 80 30 (18) 22 1.12 1 0.03 33 42 100 98 (22) 22 2.24 1 0.03 63 60 100 100 (0) 22 0.28 1 0.14 5 20 10 2 0 (75) (50) 22 0.28 1 0.14 5 17 95 90 (71) 22 0.56 1 0.14 10 12 100 85 (17) 22 1.12 1 0.14 10 38 80 100 (74) (20) 22 1.12 1 0.14 75 98 100 100 (24) (0) 22 1.12 1 0.14 90 78 75 95 (22) 22 1.12 1 0.14 30 42 100 98 (29) 22 2.24 1 0.14 43 60 100 100 (29) (0) 22 0.28 1 0.56 5 2 0 10 20 (75) (50) 22 0.28 1 0.56 15 17 95 90 (12) 22 0.56 1 0.56 5 12 80 85 (59) (6) 22 1.12 1 0.56 0 38 100 100 (100) (0) 22 1.12 1 0.56 45 98 100 100 (55) (0) 22 1.12 1 0.56 10 42 100 98 (77) 22 1.12 1 0.56 80 78 25 95 (74) 22 2.24 1 0.56 30 60 100 100 (50) (0) 22 0.28 1 2.24 10 20 10 20 (50) (50) 22 0.28 1 2.24 5 17 90 90 (71) (0) 22 0.56 1 2.24 0 12 100 85 (100) 22 1.12 1 2.24 10 38 100 100 (74) (0) 22 1.12 1 2.24 30 98 100 100 (70) (0) 22 1.12 1 2.24 70 78 85 95 (11) (11) 23 0.14 1 0.56 38 99 60 55 (62) 23 0.56 1 0.56 99 100 70 70 (1) (0) 23 0.03 1 1.12 0 0 23 0.03 1 1.12 0 55 15 15 25 (40) 23 0.14 1 1.12 45 58 50 50 85 83 (23) (0) 23 0.14 1 1.12 0 68 10 75 (100) (87) 23 0.14 1 2.24 53 99 75 55 (47) 23 0.56 1 2.24 99 100 70 70 (1) (0) 23 0.03 1 4.48 0 0 23 0.03 1 4.48 10 10 15 5 25 (34) (80) 23 0.14 1 4.48 10 58 75 50 80 83 (83) (4) 23 0.14 1 4.48 5 68 0 75 (93) (100) 23 0.14 1 8.96 73 99 60 55 (27) 23 0.56 1 8.96 99 100 70 70 (1)(0) 24 0.28 1 0.14 25 15 100 100 80 63 (0) 24 1.12 1 0.14 95 92 100 100 95 95 (0) (0) 24 0.28 1 0.56 40 15 100 100 55 63 (0) (13) 24 1.12 1 0.56 85 92 100 100 95 95 (8) (0) (0) 24 0.28 1 2.24 10 15 100 100 75 63 (34) (0) 24 1.12 1 2.24 70 92 100 100 95 95 (24) (0) (0) 25 0.14 1 0.56 10 60 35 38 (84) (8) 25 0.14 1 0.56 10 43 50 35 90 92 (77) (3) 25 0.56 1 0.56 95 85 95 77 25 0.56 1 0.5695 95 95 80 95 95 (0) (0) 25 0.14 1 1.12 80 23 15 48 90 52 (69) 25 0.56 1 1.12 95 95 90 95 95 95 (0) (6) (0) 25 0.14 1 2.24 35 60 70 38 (42) 25 0.14 1 2.24 35 43 60 35 90 92 (19) (3) 25 0.56 1 2.24 90 85 90 77 25 0.56 1 2.2495 95 95 80 100 95 (0) 25 0.14 1 4.48 25 23 0 48 85 52 (100) 25 0.56 1 4.48 95 95 95 95 95 95 (0) (0) (0) 25 0.14 1 8.96 45 60 45 38 (25) 25 0.14 1 8.96 0 43 0 35 10 92 (100) ( 100) (90) 25 0.56 1 8.96 65 95 70 80 95 95 (32) (13) (0) 25 0.56 1 8.96 10 85 85 77 (89) 26 0.03 1 1.12 95 95 95 95 (0) (0) 26 0.07 1 1.12 80 95 80 60 (16) 26 0.07 1 1.12 15 95 100 83 10 (85) 26 0.14 1 1.12 95 98 95 95 (4) (0) 26 0.28 1 1.12 90 95 100 97 35 68 (6) (49) 26 0.28 1 1.12 95 100 90 55 (5) 26 0.03 1 4.48 95 95 95 95 (0) (0) 26 0.07 1 4.48 5 95 75 83 0 (95) (10) 26 0.07 1 4.48 10 95 20 60 (90) (67) 26 0.14 1 4.48 95 98 95 95 (4) (0) 26 0.28 1 4.48 0 95 100 97 0 68 (100) (100) 26 0.28 1 4.48 90 100 90 55 (10) 27 0.14 1 0.56 0 8 70 70 (100) (0) 27 0.56 1 0.56 88 97 80 85 (10) (6) 27 1.12 1 0.56 70 70 0 7 (0) (100) 27 2.24 1 0.56 70 73 0 30 (5) (100) 27 0.14 1 1.12 0 12 15 40 (100) (63) 27 0.56 1 1.12 75 5 3 70 65 27 0.14 1 2.24 0 8 70 70 (100) (0) 27 0.56 1 2.24 43 97 85 85 (56) (0) 27 1.12 1 2.24 60 70 0 7 (15) (100) 27 2.24 1 2.24 100 73 40 30 27 0.14 1 4.48 0 12 45 40 (100) 27 0.56 1 4.48 30 53 75 65 (44) 27 0.14 1 8.96 0 8 75 70 (100) 27 0.56 1 8.96 8 97 75 85 (92) (12) 27 1.12 1 8.96 80 70 20 7 27 2.24 1 8.96 90 73 35 30 28 0.00 1 1.1210 43 25 70 0 18 (77) (65) (100) 28 0.01 1 1.12 75 95 80 75 65 75 (22) (14) 28 0.01 1 1.12 5 10 85 75 (50) 28 0.07 1 1.12 5 48 90 88 (90) 28 0.28 1 1.12 96 98 5 5 (4) (0) 28 1.12 1 1.12 100 100 50 60 (0) (17) 28 0.004 1 4.48 5 43 95 70 0 18 (89) (100) 28 0.01 1 4.48 60 95 80 75 15 75 (37) (80) 28 0.01 1 4.48 0 10 75 75 (100) (0) 28 0.07 1 4.48 10 48 90 88 (80) 28 0.28 1 4.48 95 98 15 5 (4) 28 1.12 1 4.48 100 100 55 60 (0) (9) 29 0.01 1 1.12 0 27 95 73 (100) 29 0.07 1 1.12 85 70 95 95 (0) 29 0.28 1 1.12 10 63 85 55 (85) 29 0.56 1 1.12 95 95 100 100 35 10 (0) (0) 29 1.12 1 1.12 65 93 90 90 (31) (0) 29 1.12 1 1.12 90 95 100 98 0 12 (6) (100) 29 0.01 1 4.48 50 27 85 73 29 0.07 1 4.48 25 70 90 95 (65) (6) 29 0.28 1 4.48 5 63 70 55 (93) 29 0.56 1 4.48 10 95 70 100 0 10 (90) (30) (100) 29 1.12 1 4.48 60 95 100 98 10 12 (37) (17) 29 1.12 1 4.48 20 93 100 90 (79) 29 0.01 1 0.14 40 40 15 7 (0) 30 0.03 1 0.14 50 50 0 12 (0) (100) 30 0.01 1 0.56 0 40 25 7 (100) 30 0.03 1 0.56 0 50 0 12 (100) (100) 30 1.12 1 1.12 30 93 100 100 (68) (0) 30 1.12 1 1.12 35 88 100 100 5 40 (61) (0) (88) 30 4.48 1 1.12 30 97 100 100 (70) (0) 30 4.48 1 1.12 85 93 100 100 45 50 (9) (0) (10) 30 0.01 1 2.24 20 40 15 7 (50) 30 0.03 1 2.24 30 50 10 12 (40) (17) 30 1.12 1 4.48 10 9 3 100 100 (90) (0) 30 1.12 1 4.48 55 88 100 100 0 40 (38) (0) (100) 30 4.48 1 4.48 80 93 100 100 25 50 (14) (0) (50) 30 4.48 1 4.48 65 97 100 100 (33) (0) 31 0.14 1 0.56 80 85 0 28 (6) (100) 31 0.14 1 0.56 0 40 35 31 0.14 1 0.56 80 60 35 32 100 100 (0) 31 0.56 1 0.56 30 75 60 80 (60) (25) 31 0.56 1 0.56 90 90 30 50 (0) (40) 31 0.56 1 0.56 95 90 60 95 100 100 (37) (0) 31 0.14 1 2.24 0 35 35 (0) 31 0.14 1 2.24 0 60 50 32 80 100 (100) (20) 31 0.14 1 2.24 60 85 80 28 (30) 31 0.56 1 2.24 85 90 70 95 100 100 (6) (27) (0) 31 0.56 1 2.24 90 90 45 50 (0) (10) 31 0.56 1 2.24 0 75 35 80 (100) (57) 31 0.14 1 8.96 35 60 10 32 75 100 (42) (69) (25) 31 0.14 1 8.96 0 55 35 31 0.14 1 8.96 70 85 60 28 (18) 31 0.56 1 8.96 95 90 55 95 100 100 (43) (0) 31 0.56 1 8.96 95 90 65 50 31 0.56 1 8.96 0 75 70 80 (100) (13) 23 0.03 2 1.12 20 40 15 30 25 23 0.14 2 1.12 35 58 65 50 90 83 (40) 23 0.03 2 4.48 0 0 15 35 25 (100) 23 0.14 2 4.48 35 58 55 50 15 83 (40) (82) 25 0.14 2 1.12 25 23 75 48 85 52 25 0.56 2 1.12 95 95 85 95 95 95 (0) (11) (0) 25 0.14 2 4.48 90 23 85 48 90 52 25 0.56 2 4.48 95 95 95 95 95 95 (0) (0) (0) 27 0.14 2 1.12 0 12 65 40 (100) 27 0.56 2 1.12 60 53 70 65 27 0.14 2 4.48 0 12 70 40 (100) 27 0.56 2 4.48 5 53 75 65 (91) 6 8.96 3 0.14 5 13 95 95 (62) (0) 6 11.20 3 0.14 5 30 95 95 (84) (0) 6 8.96 3 0.56 10 13 95 95 (24) (0) 6 11.20 3 0.56 0 30 95 95 (100) (0) 6 8.96 3 2.24 0 13 95 95 (100) (0) 6 11.20 3 2.24 0 30 95 95 (100) (0) 2 0.56 3 0.03 75 98 98 100 (24) (2) 2 0.56 3 0.03 75 98 95 100 (24) (5) 2 2.24 3 0.03 95 98 100 100 ( 4) (0) 2 2.24 3 0.03 93 98 100 100 (6) (0) 2 0.28 3 0.14 0 85 90 100 (100) (10) 2 0.56 3 0.14 10 93 100 100(90) (0) 2 0.56 3 0.14 85 98 100 100 (14) (0) 2 0.56 3 0.14 43 98 100 100 (57) (0) 2 0.56 3 0.14 5 75 100 98 (94) 2 2.24 3 0.14 55 98 100 100 (44) (0) 2 2.24 3 0.14 95 98 100 100 (4) (0) 2 2.24 3 0.14 95 98 100 100 (4) (0) 2 2.24 3 0.14 25 97 100 100 (75) ( 0) 2 0.28 3 0.56 0 85 95 100 (100) (5) 2 0.56 3 0.56 20 93 95 100 (79) (5) 2 0.56 3 0.56 78 98 98 100 (21) (2) 2 0.56 3 0.56 55 98 100 100 (44) (0) 2 0.56 3 0.56 5 75 90 98 (94) (9) 2 0.56 3 0.56 55 72 100 95 (24) 2 2.24 3 0.56 5 100 95 100 (95) (5) 2 2.24 3 0.56 50 98 100 100 (49) (0) 2 2.24 3 0.56 95 95 100 100 (4) (0) 2 2.24 3 0.56 90 98 100 100 (9) (0) 2 2.24 3 0.56 55 97 100 100 (44) (0) 2 3 0.56 5 50 2 0.28 3 2.24 0 85 95 100 (100) (5) 2 0.56 3 2.24 0 93 100 100 (100) (0) 2 0.56 3 2.24 15 75 95 98 (80) ( 4) 2 0.56 3 2.24 10 72 90 95 (87) (6) 2 2.24 3 2.24 20 1 00 95 100 (80) (5) 2 2.24 3 2.24 10 98 100 100 (90) (0) 2 2.24 3 2.24 50 97 100 100 (49) (0) 2 0.56 3 8.96 20 72 100 95 (73) 2 2.24 3 8.96 25 100 100 100 (75) (0) 15 1.12 3 0.56 10 10 60 50 (0) 15 1.12 3 0.56 0 10 100 90 (100) 15 4.48 3 0.56 15 35 75 50 (58) 15 4.48 3 0.56 35 75 100 100 (54) (0) 15 1.12 3 2.24 10 10 80 90 (0) (12) 15 1.12 3 2.24 0 10 75 5 0 (100) 15 4.48 3 2.24 35 35 90 50 (29) 15 4.48 3 2.24 30 75 100 100 (60) (0) 15 1.12 3 8.96 0 10 55 90 (100) (39) 15 1.12 3 8.96 0 10 25 50 (100) (50) 15 4.48 3 8.96 0 35 30 50 (100) (40) 15 4.48 3 8.96 20 75 95 100 (74) (5) 7 0.14 3 0.56 95 90 100 9 0 7 0.56 3 0.56 100 100 100 100 (0) (0) 7 1.12 3 0.56 70 72 100 100 (3) (0) 7 4.48 3 0.56 95 95 100 100 (0) (0) 7 0.14 3 2.24 70 90 95 90 (23) 7 0.56 3 2.24 100 100 100 100 (0) (0) 7 1.12 3 2.24 90 72 100 100 (0) 7 4.48 3 2.24 100 95 100 100 (0) 7 0.14 3 8.96 75 90 100 90 (17) 7 0.56 3 8.96 100 100 100 100 (0) (0) 7 1.12 3 8.96 90 72 100 100 (0) 7 4.48 3 8.96 100 95 100 100 (0) 16 0.56 3 0.56 10 20 40 100 90 (50) 16 2.24 3 0.56 35 20 95 95100 100 (0) (0) 16 0.56 3 2.24 0 35 40 100 90 (13) 16 2.24 3 2.24 30 20 85 95 100 100 (11) (0) 16 0.56 3 8.96 5 0 40 95 90 (100) 16 2.24 3 8.96 50 20 90 95 100 100 (6) (0) 17 1.68 3 0.14 88 88 100 100 (0) (0) 17 3.36 3 0.14 93 95 100 100 (3) (0) 17 1.68 3 0.56 60 88 98 100 (32) (2) 17 3.36 3 0.56 90 95 100 100 (6) (0) 17 1.68 3 2.24 88 88 100 100 (0) (0) 17 3.36 3 2.24 95 95 100 100 (0) (0) 18 0.56 3 0.56 100 78 95 97 (3) 18 1.12 3 0.56 60 42 100 100 (0) 18 2.24 3 0.56 100 97 100 100(0) 18 4.48 3 0.56 70 80 100 100 (13) (0) 18 0.56 3 2.24 30 78 100 97 (62) 18 1.12 3 2.24 45 42 100 100 (0) 18 2.24 3 2.24 95 97 100 100 (3) (0) 18 4.48 3 2.24 65 80 100 1 00 (19) (0) 18 0.56 3 8.96 95 78 100 97 18 1.12 3 8.96 60 42 100 100 (0) 18 2.24 3 8.96 90 97 100 100 (8) (0) 18 4.48 3 8.96 70 80 100 100 (13) (0) 19 0.009 3 1.12 85 90 60 88 (6) (32) 19 0.01 3 1.12 5 90 90 85 (95) 19 0.03 3 1.12 95 90 95 95 (0) 19 0.03 3 1.120 30 95 95 (100) (0) 19 0.07 3 1.12 35 97 85 90(64) (6) 19 0.14 3 1.12 65 70 95 95 (8) (0) 19 0.009 3 4.48 95 90 80 88 (10) 19 0.01 3 4.48 10 90 95 85 (89) 19 0.03 3 4.48 90 90 95 95 (0) (0) 19 0.03 3 4.48 0 30 100 95 (100) 19 0.07 3 4.48 15 97 90 90 (85) (0) 19 0.14 3 4.48 10 7 0 95 95 (86) (0) 20 0.004 3 1.12 10 12 60 10 (17) 20 0.004 3 1.12 0 22 65 25 0 10 (100) (100) 20 0.004 3 1.12 60 30 25 27 (8) 20 0.009 3 1.12 90 60 45 42 20 0.009 3 1.12 95 73 90 35 40 68 (42) 20 0.009 3 1.12 0 38 70 40 (100) 20 0.004 3 4.48 0 12 70 10 (100) 20 0.004 3 4.48 15 2 2 70 25 0 10 (32) (100) 20 0.004 3 4.48 100 30 30 27 20 0.009 3 4.48 75 73 90 35 10 68 (86) 20 0.009 3 4.48 90 60 55 42 20 0.009 3 4.48 45 38 95 40 21 0.28 3 0.14 35 47 10 35 ( 26) (72) 21 0.56 3 0.14 50 68 30 30 (27) (0) 21 1.12 3 0.14 65 67 55 30 (3) 21 0.28 3 0.56 50 47 15 35 (58) 21 0.56 3 0.56 25 68 65 30 (64) 21 1.12 3 0.56 80 67 60 30 21 0.28 3 2.24 10 47 15 35 (79) (58) 21 0.56 3 2.24 30 68 35 30 (56) 21 1.12 3 2.2470 67 25 30 (17) 21 0.28 3 8.96 40 47 25 35 (15) (29) 21 0.56 3 8.9660 68 10 30 (12) (67) 21 1.12 3 8.96 15 67 65 30 (78) 22 1.12 3 0.03 20 42 100 98 (53) 22 2.24 3 0.03 40 60 100 100 (34) ( 0) 22 0.28 3 0.14 70 20 25 20 22 0.28 3 0.14 5 17 100 90 (71) 22 0.56 3 0.14 10 12 100 85 (17) 22 1.12 3 0.14 15 38 90 100 (61) (10) 22 1.12 3 0.14 45 78 35 95 (43) (64) 22 1.12 3 0.14 35 98 100 100 (65) (0) 22 1.12 3 0.14 35 42 100 98 (17) 22 2.24 3 0.14 58 60 100 100 (4) (0) 22 0.28 3 0.56 15 17 90 90 (12) (0) 22 0.28 3 0.56 10 20 25 20 (50) 22 0.56 3 0.56 5 12 90 85 ( 59) 22 1.12 3 0.56 10 78 35 95 (88) (64) 22 1.12 3 0.56 10 38 100 100 (74) (0) 22 1.12 3 0.56 85 98 100 100 (14) (0) 22 1.12 3 0.56 5 42 100 98 (89) 22 2.24 3 0.56 38 60 100 100 (37) (0) 22 0.28 3 2.24 0 17 90 90 (100) (0) 22 0.28 3 2.24 10 20 15 20 (50) (25) 22 0.56 3 2.24 0 12 100 85 (100) 22 1.12 3 2.24 10 38 100 100 (74) (0) 22 1.12 3 2.24 75 78 80 95(4) (16) 22 1.12 3 2.24 40 98 100 100 (60) (0) 23 0.03 3 0.56 10 25 5 25 (60) (80) 23 0.03 3 0.56 25 35 95 65 15 45 (29) (67) 23 0.14 3 0.56 25 95 100 90 85 97 (74) (13) 23 0.14 3 0.56 58 99 60 55 (42) 23 0.14 3 0.56 70 80 50 50 (13) (0) 23 0.56 3 0.56 90 100 70 70 (10) (0) 23 0.03 3 1.12 5 0 23 0.03 3 1.12 0 60 15 35 25 23 0.14 3 1.12 20 58 50 50 40 83 (66) (0) (52) 23 0.14 3 1.12 5 68 35 75 (93) (54) 23 0.03 3 2.24 10 35 80 65 0 45 (72) (100) 23 0.03 3 2.24 5 25 5 25 (80) (80) 23 0.14 3 2.24 70 80 30 50 (13) (40) 23 0.14 3 2.24 23 99 35 55 (77) (37) 23 0.14 3 2.24 90 95 100 90 100 97 (6) 23 0.56 3 2.24 85 100 70 70 (15)(0) 23 0.03 3 4.48 0 50 23 0.03 3 4.48 5 60 15 0 25 (100) 23 0.14 3 4.48 0 58 40 50 85 83 (100) (20) 23 0.14 3 4.48 0 68 15 75 (100) (80) 23 0.03 3 8.96 15 25 15 25 (40) (40) 23 0.03 3 8.96 15 35 80 65 0 45 (58) (100) 23 0.14 3 8.96 55 95 100 90 85 97 (43) (13) 23 0.14 3 8.96 55 80 45 50 (32) (10) 23 0.14 3 8.96 12 99 50 55 (88) (10) 23 0.56 3 8.96 95 100 70 70 (5) (0) 24 0.28 3 0.14 15 15 100 100 80 63 (0) (0) 24 1.12 3 0.14 70 92 100 100 95 95 (24) (0) (0) 24 0.28 3 0.56 15 15 100 100 60 63 (0) (0) (5) 24 1.12 3 0.56 95 92 100 100 95 95 (0) (0) 24 0.28 3 2.24 10 15 100 100 80 63 (34) (0) 24 1.12 3 2.24 95 92 100 100 95 9 5 (0) (0) 25 0.14 3 0.56 55 60 40 38 (9) 25 0.14 3 0.56 30 43 75 35 65 92 (31) ( 30) 25 0.28 3 0.56 95 82 100 98 25 0.28 3 0.56 70 92 50 60 (24) (17) 25 0.56 3 0.56 95 95 75 80 95 95 (0) (7) (0) 25 0.56 3 0.56 90 85 95 77 25 1.12 3 0.56 100 100 100 100 (0) (0) 25 1.12 3 0.56 100 100 80 70 (0) 25 0.14 3 1.12 70 23 20 48 90 52 (59) 25 0.56 3 1.12 100 95 80 95 95 95 (16) (0) 25 0.14 3 2.24 0 43 10 35 25 92 (100) (72) (73) 25 0.14 3 2.24 100 60 40 38 25 0.28 3 2.24 90 82 95 98 (4) 25 0.28 3 2.24 90 92 85 60 (3) 25 0.56 3 2.24 80 85 85 77 (6) 25 0.56 3 2.24 95 95 90 80 95 95 (0) (0) 25 1.12 3 2.24 100 100 95 100 (0) (5) 25 1.12 3 2.24 100 100 80 70 (0) 25 0.14 3 4.48 80 23 75 48 95 52 25 0.56 3 4.48 95 95 85 95 95 95 (0) (11) (0) 25 0.14 3 8.96 30 43 75 3 5 50 92 (31) (46) 25 0.14 3 8.96 90 60 30 38 (22) 25 0.28 3 8.96 95 92 85 60 25 0.28 3 8.96 95 82 95 98 (4) 25 0.56 3 8.96 85 95 90 8095 95 (11) (0) 25 0.56 3 8.96 90 85 80 77 25 1.12 3 8.96 100 100 100 100 (0) (0) 25 1.12 3 8.96 100 100 80 70 (0) 32 2.24 3 0.56 20 10 15 55 (73) 32 4.48 3 0.56 15 40 60 55 (63) 32 2.24 3 2.24 40 1 0 75 55 32 4.48 3 2.24 10 40 70 55 (75) 32 2.24 3 8.96 20 10 80 55 32 4.48 3 8.96 15 40 80 55 (63) 26 0.03 3 1.12 90 95 95 95 (6) (0) 26 0.07 3 1.12 15 9 5 70 83 15 (85) (16) 26 0.07 3 1.12 10 95 75 60 (90) 26 0.14 3 1.12 95 98 95 95 (4) ( 0) 26 0.28 3 1.12 95 95 95 97 40 68 (0) (3) (42) 26 0.28 3 1.12 95 100 75 55 (5) 26 0.03 3 4.48 95 95 95 95 (0) (0) 26 0.07 3 4.48 20 95 0 83 10 (79) (100) 26 0.07 3 4.48 5 95 80 60 (95) 26 0.14 3 4.48 95 98 95 95 (4) (0) 26 0.28 3 4.48 90 100 100 55 (10) 26 0.28 3 4.48 90 95 100 97 5 68 (6) (93) 27 0.14 3 0.56 90 98 90 95 90 98 (9) (6) (9) 27 0.14 3 0.56 0 8 75 70 ( 100) 27 0.56 3 0.56 95 100 100 100 95 100 (5) (0)(5) 27 0.56 3 0.56 53 97 85 85 (46) (0) 27 0.56 3 0.56 60 90 70 80 (34) (13) 27 1.12 3 0.56 85 97 85 80 (13) 27 1.12 3 0.56 80 70 0 7 (100) 27 2.24 3 0.56 70 73 20 30 (5) (34) 27 0.14 3 1.12 0 12 75 40 (100) 27 0.56 3 1.12 10 53 60 65 (82) (8) 27 0.14 3 2.24 0 8 70 70 (100) (0) 27 0.14 3 2.24 95 98 95 95 95 98 (4) (0) ( 4) 27 0.56 3 2.24 15 97 80 85 (85) (6) 27 0.56 3 2.24 100 100 100 100 95 100 (0) (0) (5) 27 0.56 3 2.24 65 90 90 80 (28) 27 1.12 3 2.24 75 97 70 80 (23) (13) 27 1.12 3 2.24 90 70 5 7 (29) 27 2.24 3 2.24 65 73 20 30 (11) (34) 27 0.14 3 4.48 0 12 60 40 (100) 27 0.56 3 4.48 20 53 75 65 (63) 27 0.14 3 8.96 100 98 100 95 90 98(9) 27 0.14 3 8.96 0 8 75 70 (100) 27 0.56 3 8.96 28 97 85 85 (72) (0) 27 0.56 3 8.96 100 100 100 100 100 100 (0) (0) (0) 27 0.56 3 8.96 30 90 70 80 (67) (13) 27 1.12 3 8.96 90 97 95 80 (8) 27 1.12 3 8.96 75 70 20 7 27 2.24 3 8.96 65 73 20 30 (11) (34) 28 0.004 3 1.12 40 43 70 70 10 18 (7) (0) (45) 28 0.01 3 1.12 0 10 60 75 (100)(20) 28 0.01 3 1.12 65 95 85 75 25 75 (32) (67) 28 0.07 3 1.12 5 48 85 88 (90) (4) 28 0.28 3 1.12 95 98 5 5 (4) (0) 28 1.12 3 1.12 100 100 5 60 (0) (92) 28 0.004 3 4.48 10 43 85 70 0 18 (77) (100) 28 0.01 3 4.48 85 95 90 75 10 75 (11) (87) 28 0.01 3 4.48 0 10 70 75 (100) (7) 28 0.07 3 4.48 0 48 90 88 (100) 28 0.28 3 4.48 95 98 5 5 (4) (0) 28 1.12 3 4.48 95 100 75 60 (5) 29 0.01 3 1.12 0 27 95 73 (100) 29 0.07 3 1.12 75 70 100 95 29 0.28 3 1.12 0 63 90 55 (100) 29 0.56 3 1.12 70 95 100 100 0 10 (27) (0) (100) 29 1.12 3 1.12 80 95 100 98 0 12 (16) (100) 29 1.12 3 1.12 30 93 80 90 (68) (12) 29 0.01 3 4.48 70 27 75 73 29 0.07 3 4.48 0 70 95 95 (100) (0) 29 0.28 3 4.48 5 63 80 55 (93) 29 0.56 3 4.48 80 95 100 100 0 10 (16) (0) (100) 29 1.12 3 4.48 85 95 100 98 0 12 (11) (100) 29 1.12 3 4.48 15 93 100 90 (84) 30 0.01 3 0.14 0 40 20 7 (100) 30 0.03 3 0.14 50 50 0 12 (0) (100) 30 0.01 3 0.56 60 40 20 7 30 0.03 3 0.56 35 50 20 12 (30) 30 1.12 3 1.12 45 88 100 100 5 40 (49) (0) (88) 30 1.12 3 1.12 30 93 100 100 (68) (0) 30 4.48 3 1.12 95 93 100 100 55 50 (0) 30 4.48 3 1.12 50 97 100 100(49) (0) 30 0.01 3 2.24 0 40 0 7 (100) (100) 30 0.03 3 2.24 70 50 25 12 30 1.12 3 4.48 5 93 100 100 (95) (0) 30 1.12 3 4.48 70 88 100 100 0 40 (21) (0) (100) 30 4.48 3 4.48 45 97 100 100 (54) (0) 30 4.48 3 4.48 95 93 100 100 75 50 (0) 31 0.14 3 0.56 60 60 10 32 95 100 (0) (69) (5) 31 0.14 3 0.56 90 85 45 28 31 0.14 3 0.56 0 75 35 31 0.56 3 0.56 10 75 70 80 (87) (13) 31 0.56 3 0.56 90 90 80 50 (0) 31 0.56 3 0.56 95 9095 95 100 100 (0) (0) 31 0.14 3 2.24 95 85 5 28 (83) 31 0.14 3 2.24 60 60 40 32 100 100 (0) (0) 31 0.14 3 2.24 0 65 35 31 0.56 3 2.24 15 75 80 80 (80) (0) 31 0.56 3 2.24 90 90 30 50 (0) (40) 31 0.56 3 2.24 75 90 95 95 100 100 (17) (0) (0) 31 0.14 3 8.96 50 60 0 32 85 100 (17) (100) (15) 31 0.14 3 8.9690 85 80 28 31 0.14 3 8.96 0 65 35 31 0.56 3 8.96 25 75 65 80 (67) (19) 31 0.56 3 8.96 95 90 90 50 31 0.56 3 8.96 90 90 30 95 100 100 (0) (69) (0) 33 0.56 3 0.56 0 17 90 95 30 7 10 8 13 25 (100) (6) (48) 33 1.12 3 0.56 10 85 95 100 40 17 30 35 58 78 (89) (5) (15) (26) 33 2.24 3 0.56 60 87 100 100 40 9 3 50 32 100 100 (32) (0) (57) (0) 33 0.56 3 2.24 10 17 95 95 13 7 0 8 10 25 (42) (0) (100) (60) 33 1.12 3 2.24 45 85 100 100 73 17 55 35 58 78 (48) (0) (26) 33 2.24 3 2.24 63 87 100 100 58 93 35 32 78 100 (28) (0) (38) (22) 33 0.56 3 8.96 13 17 95 95 10 7 13 8 40 25 (24) (0) 33 1.12 3 8.96 10 85 100 100 0 17 40 35 92 78 (89) (0) (100) 33 2.24 3 8.96 25 87 100 100 40 93 10 32 73 100 (72) (0) (57) (69) (27) 23 0.03 13 1.12 0 50 15 40 25 23 0.14 13 1.12 45 58 65 50 90 83 (23) 23 0.03 13 4.48 0 40 15 25 25 (0) 23 0.14 13 4.48 10 58 35 50 80 83 (83) (30) (4) 25 0.14 13 1.12 10 23 25 48 35 52 (57) (48) (33) 25 0.56 13 1.12 95 95 90 95 95 95 (0) (6) (0) 25 0.14 13 4.48 20 23 50 48 90 52 (14) 25 0.56 13 4.48 95 95 75 95 95 95 (0) (22) (0) 27 0.14 13 1.12 0 12 65 40 (100) 27 0.56 13 1.12 25 53 80 65 (53) 27 0.14 13 4.48 0 12 70 40 (100) 27 0.56 13 4.48 5 53 75 65 (91) 19 0.009 27 1.12 90 90 75 88 (0) (15) 19 0.01 27 1.12 0 90 70 85 (100) (18) 19 0.03 27 1.12 90 90 95 95 (0) (0) 19 0.03 27 1.12 0 30 95 95 (100) (0) 19 0.07 27 1.12 5 97 85 90 (95) (6) 19 0.14 27 1.12 85 70 95 95 (0) 19 0.009 27 4.48 85 90 95 88 (6) 19 0.01 27 4.48 10 90 85 85 (89) (0) 19 0.03 27 4.48 95 90 95 95 (0) 19 0.03 27 4.48 0 30 95 95 (100) (0) 19 0.07 27 4.48 25 97 85 90(75) (6) 19 0.14 27 4.48 5 70 90 95 (93) (6) 20 0.004 27 1.12 0 22 15 25 0 10 (100) (40) (100) 20 0.004 27 1.12 0 12 40 10 (100) 20 0.004 27 1.12 65 30 35 27 20 0.009 27 1.12 95 73 60 35 30 68 (56) 20 0.009 27 1.12 25 60 50 42 (59) 20 0.009 27 1.12 0 38 55 40 (100) 20 0.004 27 4.48 40 3 0 45 27 20 0.004 27 4.48 0 12 25 10 (100) 20 0.004 27 4.48 0 22 0 25 10 10 (100) (100) (0) 20 0.009 27 4.48 0 38 50 40 (100) 20 0.009 27 4.48 95 73 55 35 15 68 (78) 20 0.009 27 4.48 55 60 35 42 (9) (17) 26 0.03 27 1.12 80 95 95 95 (16) (0) 26 0.07 27 1.12 15 95 100 60 (85) ##STR44##
EXAMPLE 44
The procedure described in Example 42 was used to conduct tests for the antidotal activity of the compound of Example 3 (oxazolidine, 3-(dichloroacetyl)-5-(2-furanyl)-2,2-dimethyl-)with a thiocarbamate herbicide (2,3,3-)trichloroalkyl-N,N-diisopropylthiocarbamate, (triallate); Herbicide No. 1) and a herbicidal pyridine compound (3-pyridinecarboxylic acid, 2-(difluoromethyl)-5-(4,5-dihydro-2-thiazolyl)-4-(2-methylpropyl)-6-trifluoromethyl)-, methyl ester; Herbicide No. 24). Results are reported in Table 7.
TABLE 7 % PLANT INHIBITION AND % SAFENING EFFECT ( ) Barnyard Sorghum Foxtail Pigweed Velvet Hemp Indian Tartary HERB. ANTIDOTE Corn Grass (Grain) Green Redroot Leaf Soybean Wheat Rice Sesbania Mustard Buckwheat NO. RATE NO. RATE W WO W WO W WO W WO W WO W WO W WO W WO W WO W WO W WO W WO 1 1.12 3 0.03 100 100 93 98 (0) (6) 1 0.28 3 0.12 98 100 20 62 (2) (68) 1 1.12 3 0.12 100 100 95 98 (0) (4) 1 0.28 3 0.50 100 100 0 62 (0) (100) 1 1.12 3 0.50 100 100 85 98 (0) (14) 24 0.01 3 0.03 0 5 7 80 65 (29) 24 0.07 3 0.03 0 10 15 95 95 (100) (0) 24 0.28 3 0.03 0 3 60 33 100 100 (100) (0) 24 0.01 3 0.03 0 20 68 85 98 98 (100) (20) (0) 24 0.07 3 0.03 65 72 90 97 100 100 (10) (8) (0) 24 0.28 3 0.03 100 100 100 100 100 100 (0) (0) (0) 24 0.01 3 0.12 15 20 80 85 98 98 (25) (6) (0) 24 0.01 3 0.12 10 28 7 50 65 (24) 24 0.07 3 0.12 0 10 8 95 95 (100) (0) 24 0.07 3 0.12 60 72 98 97 100 100 (17) (0) 24 0.28 3 0.12 93 100 100 100 100 100 (7) (0) (0) 24 0.28 3 0.12 0 3 75 33 100 100 (100) (0) 24 0.01 3 0.50 35 20 40 85 100 98 ( 53) 24 0.01 3 0.50 5 20 7 80 65 24 0.07 3 0.50 30 72 100 97 100 100 (59) (0) 24 0.07 3 0.50 0 10 60 95 95 (100) (0) 24 0.28 3 0.50 90 100 98 100 100 100 (10) (2) (0) 24 0.28 3 0.50 0 3 70 33 95 100 (100) (5)
EXAMPLE 45
This example describes the preparation of the herbicidal compound 5-(trifluoromethyl)-4-chloro-3-(3'-[1-ethoxycarbonyl]-ethoxy-4'-nitrophenoxy)-1-methylpyrazole (Herbicide No. 34), a heterocycyl phenyl ether compound representative of the class.
961 g (4.80 mol) of 5-trifluoromethyl-4-chloro-3-hydroxy-1-methylpyrazol, 1317 g (5.12 mol) of ethyl 2-(5-fluoro-2-nitrophenoxy)propanoate, and 380 g (2.75 mol) of potassium carbonate were stirred with 6000 ml of DMSO at 70° C. for 20 hours. Another 100 g (0.72 mol) of potassium carbonate was added. After another 16 hours at 70° C. another 163 g (1.18 mol) of potassium carbonate was added. After stirring another 6 hours at 70° C., the product was isolated from the mixture by extracting twice with ether and combining the ether extracts, washing same 2× with brine, dried with MgSO 4 , decolorized with charcoal, filtered and rotovaped to give a black oil. Purification by silica gel chromatography gave 1733 g of a dark oil. Further, purification by vacuum distillation (molecular still) gave a reddish orange solid, m.p. 40°-44° C.
______________________________________Elemental Analysis for C.sub.16 H.sub.15 F.sub.3 Cl.sub.1 N.sub.3O.sub.6 C H N______________________________________Calculated 43.90 3.45 9.60Found 43.96 3.50 9.58______________________________________
The above first-names intermediate, (5-trifluoromethyl)-4-chloro-3-hydroxy-1-methylpyrazole (m.p. 136°-140° C.) may be prepared by various means. A preferred process comprises bubbling ammonia gas through ethyl 4,4,4-trifluoroacetoacetate at an elevated temperature of about 55°-85° C. while removing water to form 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester. This ester is then reacted directly with methylhydrazine at about 60°-100° C. to form the 3- and 5- hydroxy isomers mixture of the intermediate pyrazole. The desired 3- isomer may be separated by stirring the isomer mixture in an aqueous solution of sodium bicarbonate wherein the 5-isomer is dissolved while the 3-isomer remains in suspension and is readily separated by filtration. The 5-trifluoromethyl-3-hydroxy methylpyrazole product can be then chlorinated in the 4-position using a suitable chlorinating agent such as chlorine or sulfuryl chloride in a suitable solvent such as acetonitrile or diethyl ether, then poured into ice water containing sodium carbonate, washed with water and extracted with ether, and purified, e.g., by recrystallization.
The above intermediate, ethyl 2-(5-fluoro-2-nitrophenoxy) propanoate can be prepared from 2-hydroxy-4-fluoronitrobenxene which is commercially available or by reacting 2,4- difluoronitrobenzene with sodium hydroxide in dimethylsulfoxide (DMSO) and extracting the product form water with hexane. 2-hydroxy-4-fluoronitrobenzene is reacted with a haloalkylcarboxylate (e.g., ethyl 2-bromo- or 2-chloropropionate in a suitable solvent (e.g., acetone, acetonitrile, DMF or DMSO) in the presence of a base (e.g., KOH or NaOH) for an extended period (e.g., 3 days), then isolating the nitrobenzene product by standard laboratory techniques.
EXAMPLE 46
This example describes a greenhouse test for the postemergence activity of the compound of Example 3 in combination with the Herbicide No. 34, the compound of the preceding example. The test plants involved were soybeans as the crops and the weeds morningglory and velvetleaf.
The procedure used in conducting the tests of this example involved planting the test plants in separate pots and growing the soybeans to the 1.5 trifoliate stage, then applying the herbicide and tank-mixtures of the herbicide and antidote to the plant canopy (foliage) surface with the track sprayer delivering 20 gal. (75.71 liters) of liquid per acre (0.405 ha). All plants were sprayed when the soybeans reached the 1.5 trifoliate leaf stage. Observations of herbicidal activity were made thirteen (13) days after spraying the plants. Results are shown in Table 8.
TABLE 8______________________________________Treatment Rate(Kg/Ha)Ex./Anti- Herb Morning Velvetdote #3 #34 Soybeans glory leaf______________________________________0 0 0.00 0.00 0.000 0.56 21 98 980 2.24 43 99 99.035 0 5 10 1.035 .56 20 98 98.035 2.24 41 98 98.07 0 9 14 1.07 .56 16 98 99.07 2.24 21 99 99.14 0 5 8 0.14 .56 16 95 98.14 2.24 21 95 970.28 0 8 15 10.28 0.56 11 89 980.28 2.24 38 98 990.56 0 5 15 10.56 0.56 19 98 990.56 2.24 31 99 99______________________________________
As noted in the data in Table 8, soybean injury was reduced from about 21% when treated with 0.56 kg/ha of herbicide alone to about 11% when, at the same herbide rate, 0.28 kg/ha of antidote was present. Weed control was excellent for morningglory and velvetleaf. The data also indicates that for Antidote No. 3 rates of 0.28 kg/ha soybean injury due to Herbicide No. 34 was excessive. It was also observed that even at the higher antidote rates, at the time of observation all soybeans were actively growing out of their injury, whereas both weeds were mostly dead.
EXAMPLE 47
This example describes a field test evaluation of the postemergence activity of the same herbicide/antidote combination used in the greenhouse tests of Example 46.
Velvetleaf and morningglory seed (3.5 gal.; 13.251) were blended together and seeded with a cyclone spreader (setting 1.5) mounted on the tri-motorcycle (spacing every 25 ft; 7.62 meters) and incorporated into the soil (silt loam) with a culti-packer to a depth of 1.0 in. (2.54 cm). A four-row John Deere Maxi-merge planter with 20 in. (50.8 cm) row spacings was used to plant 4 rows of the soybeans (Williams) 1.0 in. (2.54 cm) in the soil.
No overhead irrigation was employed in this test as soil conditions, i.e., hot and humid with excellent soil moisture, were extremely favorable for fast soybean growth.
The soybeans were allowed to grow to the 1.5 trifoliate stage (two weeks) at which time the herbicide alone and tank mixtures of the herbicide/antidote combination were applied to the plant canopy surface with a small plot tractor-mounted sprayer delivering 30 gal. (113.56 l) of liquid per acre (0.405 ha). A randomized block design with three replicates of each treatment was used. Each plot was 12 ft×25 ft (3.66 m×7.62 m).
Evaluations ("Eval") of herbicidal activity were made 5 and 14 days after treatment (DAT). Results are shown in Table 9, in which the following symbols are used to represent plants.
TABLE 9______________________________________Treatment Rate(Kg/Ha)Eval. Herb. Ex./Anti- % Inhibition (Avg. 3 reps)(DAT) No. 4 dote #3 S MG VL P CW______________________________________ 5 0 0 0 0 0 0 014 0 0 0 0 0 0 0 5 0.0175 0 15 75 83 93 9614 0.0175 0 10 65 85 87 96 5 0.035 0 20 85 92 95 9614 0.035 0 18 77 93 95 97 5 0.07 0 27 92 97 97 9914 0.07 0 23 87 99 95 98 5 0.07 0.28 15 90 96 97 914 0.07 0.28 12 90 93 93 98______________________________________ S = Soybeans MG = Morningglory VL = Velvetleaf P = Purslane CW = Carpetweed
The results of the above field test indicate that Herbicide No. 34 is extremely active against noxious weeds even at rates as low as 0.0175 kg/ha (1/64 lb/ac). At 0.035 kg/ha (1/32 lb/ac) and without an antidote, soybean injury is slightly above commercially-desirable levels (15%), whereas weed control is excellent. At 0.07 kg/ha (1/6 lb/ac) Herbicide No. 34 caused injury to soybeans above the commercially-desirable level. However, when 0.28 kg/ha (1/4 lb/ac) of Antidote No. 3 was mixed with 0.07 kg/ha of the herbicide, soybean injury was reduced to commercially-acceptable levels with substantially complete weed control.
Sympotomology on the soybeans indicated some initial brown spotting present, but no further development of herbicide injury (severe burn). Results were more dramatic at 5 DAT than at 14 DAT when all soybean plants appeared to outgrow injury.
EXAMPLE 48
Using the same procedure described in Example 45, but substituting n-butyl 2-(5-fluoro-2-nitrophenoxy) propanoate as the starting alkoxycarbonyl alkoxy nitrobenzene, there was prepared 5-trifluoromethyl-4-chloro-3-(3'-[1-n-butoxycarbonyl] ethoxy-4'-nitrophenoxy)-1-methylpyrazol, N D 25 2.5102. (Herbicide No. 35)
EXAMPLE 49
Following the procedure described in Example 46, postemergence tests were conducted in the greenhouse to determine the antidotal activity of the compounds of Examples 3 and 20 (Antidote Nos. 3 and 20, respectively) against the heterocycl phenyl ether prepared in the preceding example, i.e., Herbicide No. 35, in soybeans; no weeds were present in this test. Observations of herbicidal activity on the whole plant were made ten days after treatment (DAT); observation of initial activity at the first trifoliate stage was made the day following treatment. Test results are shown in Table 10.
TABLE 10______________________________________ % Soybean InjuryEx./Anti- Rate Herb. #35 (Avg. 2 reps)Dote No. (Kg/Ha) (Kg/Ha) 1 DAT 10 DAT______________________________________-- -- 0.56 80 50-- -- 2.24 90 50 3 2.24 -- 15 5 3 0.14 0.56 95 50 3 0.14 2.24 90 40 3 0.56 0.56 80 35 3 0.56 2.24 90 35 3 2.24 0.56 90 35 3 2.24 2.24 90 3520 2.24 -- 20 1020 0.14 0.56 90 2820 0.14 2.24 90 2520 0.56 0.56 80 3020 0.56 2.24 90 3520 2.24 0.56 85 2520 2.24 2.24 95 35______________________________________
Neither antidote reduced initial leaf burn caused by Herbicide No. 35; however, regrowth was enhanced substantially after ten days, particularly when treated with Antidote No. 20. The 50% injury caused by the herbicide 10 DAT at 0.56 Kg/ha was reduced to 28% by 0.14 kg/ha of Antidote No. 20. Similar reductions in soybean injury were effected by other herbicide/antidote ratios with Antidote No. 20 and to a lesser extent with Antidote No. 3.
The above specifically mentioned herbicidal compounds are intended merely as exemplary of the classes of herbicides which they represent. However, it is expressly contemplated that many other herbicidal compounds analogous to those represented herein having a variety of equivalent radicals substituted on the central nucleus may similarly be safened to various crop plants to a greater or lesser extent with the antidotal compounds of this invention. For example, other α-haloacetanilide compounds useful as herbicides are described in U.S. Pat. Nos. 3,442,945, 3,547,620, 3,830,841, 3,901,768, 4,517,011, 4,601,745, 4,319,918, 3,586,496 and 3,574,746.
Herbicidally-useful thiocarbamate compounds are described in U.S. Pat. Nos. 2,913,327, 3,330,643 and 3,330,821.
Other herbicidal pyridine compounds are described in U.S. Pat. No. 4,692,184 and copending U.S. patent Ser. Nos. 07/134,231 and 07/134,232, now U.S. Pat. No. 4,826,532 both of common assignment herewith.
Herbicidally-useful heterocycyl phenyl ethers (especially pyrazolyl aryl ethers) are described in U.S. Pat. No. 4,298,749 and copending U.S. patent Ser. Nos. 07/175,460, entitled "Substituted 3-(4-Nitrophenoxy) Pyrazoles and Their Use As Herbicides", of common assignment herewith.
Herbicidal diphenyl ethers and nitrophenyl ethers include 2,4-dichlorophenyl 4'-nitrophenyl ether ("nitrofen"), 2-chloro-1-(3'-ethoxy-4'-nitrophenoxy)-4-trifluoromethylbenzene ("Oxyfluorfen"), 2',4'-dichlorophenyl 3-methoxy-4-nitrophenyl ether ("Chlormethoxynil"), methyl 2-[4'-(2", 4"-dichlorophenoxy)-phenoxy]-propionate, N-(2'-phenoxyethyl)-2-[5'-(2"-chloro-4"-trifluoromethylphenoxy)-phenoxy]-propionamide, 2-methoxyethyl 2-[nitro-5-(2-(2-chloro-4-trifluoromethylphenoxy)-phenoxyl-propionate and 2-chloro-4-trifluoromethylphenyl 3'-oxazolin-2'-yl-4'-nitrophenylether.
Another generic class of agrichemically-important herbicidal compounds specifically contemplated for use in combination with the antidotal compounds of this invention are the ureas and sulfonylurea derivatives. Important herbicidal ureas include 1-(benzothiazol-2-yl)-1,3-dimethylurea; phenylureas, for example: 3-(3-chloro-p-tolyl)-1,1-dimethylurea ("chlorotoluron"), 1,1-dimethyl-3-(α,α,αtrifluorom-tolyl)urea ("fluometuron"), 3-(4-bromo-3-chlorophenyl)methoxy-1-methylurea ("chlorbromuron"), 3-(4-bromophenyl)-1-methoxy-1-methylurea ("metobromuron"), 3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea ("linuron"), 3-(4-chlorophenyl)-1-methoxy-1-methylurea ("monolinuron"), 3-(3,4-dichlorophenyl)-1,1-dimethylurea ("diuron"), 3-(4-chlorophenyl)-1,1-dimethylurea ("monuron") and 3-(3-chloro-4-methoxyphenyl)-1,1-dimethylurea ("metoxuron");
Important herbicidal sulfonylureas specifically contemplated as useful in compositions with the antidotal compounds of this invention include those disclosed in the following patents: U.S. Pat. Nos. 4,383,113, 4,127,405, 4,481,029, 4,514,212, 4,420,325, 4,638,004, 4,675,046, 4,681,620, 4,741,760, 4,723,123, 4,411,690, 4,718,937, 4,620,868, 4,668,277, 4,592,776, 4,666,508, 4,696,695, 4,731,446 and 4,668,279 and EP Numbers 084224, 173312, 190105, 256396, 264021, 264672, 142152, 244847, 176304, 177163, 187470, 187489, 184385, 232067, 234352, 189069, 224842, 249938, 246984 and 246984.
Among the herbicidal sulfonylureas disclosed in one or more of the above patents which are of particular interest are mentioned the species N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-3-chloro-4-methoxycarbonyl-1-methylpyrazole-5-sulfonamide, N-](4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-3-chloro-4-methoxycarbonyl-1-methylpyrazole-5-sulfonamide, N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide, N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide, N[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-3-bromo-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide, N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-3-bromo-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide and N-(methoxycarbonyl-1-phenyl sulfonyl-N'-(bis-difluoromethoxy pyrimidin-2-yl)urea.
Other herbicidal imidazolinone or imidazolidinone or -dione compounds within the purview of this invention which may be safened for use in various crops include the compounds disclosed in the following exemplary publications: EP Numbers 041623, 198552 and 216360; JA 1109-790, JA 1197-580A, GB 2 172 886A, J6 1183-272A and and Australian published Application No. AU 8661-073A and U.S. Pat. Nos. 4,188,487, 4,297,128, 4,647,301, 4,638,068, 4,650,514, 4,562,257, 4,554,013, 4,709,036, 4,749,404 and 4,741,767.
Still other classes of herbicidal compounds contemplated for combination with the antidotes of this invention include the following representative species:
Triazines and triazinones: 2,4-bis-(isopropylamino)-6-methylthio-1,3,5-triazine ("prometryn"), 2,4-bis(ethylamino)-6-methylthio-1,3,5-triazine ("simetryn"), 2-(1',2'-dimethylpropylamino)-4ethylamino-6-methylthio-1,3,5-triazine ("dimethametryn"), 2-chloro-4,6-bis-(ethylamino-1,3,5-triazine ("simazine"), 2-tertbutylamino-4-chloro-6-ethylamino-1,3,5-triazine ("terbuthylazine"), 2-tert-butylamino-4-ethylamino-6-methoxy-1,3,5-triazine ("terbumeton"), 2-tertbutylamino-4-ethylamino-6-methylthio-1,3,5-triazine ("terbutryn"), 2-ethylamino-4-isopropylamino-6-methylthio-1,3,5-triazine ("ametryn") and 3,4-bis(methylamino)-6-tert-butyl-4,4-dihydro-1,2,4-triazin-5-one.
Benzoic acid derivatives: 5-(2'-chloro-4'-trifluoromethylphenoxy)-2-nitrobenzoic acid ("Acifluorfen") and 2,6-dichlorobenzonitrile ("dichlobenil").
Oxadiazolones: 5-tert-butyl-3-(2',4'-dichloro-5'-isopropoxyphenyl)-1,3,4-oxadiazol-2-one ("Oxadiazon").
Phoxphates: S-2-methylpiperidinocarbonylmethyl O,O-dipropyl phosphorodithioate ("Piperophos").
Pyrazoles: 1,3-dimethyl-4-(2',4'-dichlorobenzolyl)-5-(4'-tolylsulfonyloxy)-pyrazole.
Also α-(phenoxyphenoxy)-propionic acid derivatives and α-pyridyl-2-oxyphenoxy)-propionic acid derivatives.
As will be appreciated by those skilled in the art, the practice of this invention comprises the use of the novel antidotal compounds disclosed and claimed herein with any herbicidally-active compound. Obviously, the above listings of exemplary compounds is not intended to be exhaustive, but representative. Again, as noted earlier herein, it is expected that not every combination of herbicide and antidote will result in safening of all crops, but is within the skill of the art to test any given herbicide with an invention antidote in plant screens of any spectrum of plants and note the results.
The foregoing embodiments illustrate that the combinations of herbicide and antidote of this invention are useful in controlling weeds while reducing herbicidal injury to crop plants under greenhouse and field test conditions.
In field applications, the herbicide, antidote, or a mixture thereof, may be applied to the plant locus without any adjuvants other than a solvent. Usually, the herbicide, antidote, or a mixture thereof, is applied in conjunction with one or more adjuvants in liquid or solid form. Compositions or formulations containing mixtures of an appropriate herbicide and antidote usually are prepared by admixing the herbicide and antidote with one or more adjuvants such as diluents, solvents, extenders, carriers, conditioning agents, water, wetting agents, dispersing agents, or emulsifying agents, or any suitable combination of these adjuvants. These mixtures may be in the form of particulate solids, granules, pellets, wettable powders, dusts, solutions, aqueous dispersions, or emulsions.
Examples of suitable adjuvants are finely-divided solid carriers and extenders including talcs, clays, pumice, silica, diatomaceous earth, quartz, Fuller's earth, sulfur, powdered cork, powdered wood, walnut flour, chalk, tobacco dust, charcoal, and the like. Typical liquid diluents include Stoddard's solvent, acetone, methylene chloride, alcohols, glycols, ethyl acetate, benzene, and the like. Liquids and wettable powders usually contain as a conditioning agent one or more surface-active agents in amounts sufficient to make a composition readily dispersible in water or in oil. The term "surface-active agent" includes wetting agents, dispersing agents, suspending agents, and emulsifying agents. Typical surface-active agents are mentioned in U.S. Pat. No. 2,547,724.
Compositions of this invention generally contain from about 5 to 95 parts herbicide-and-antidote, about 1 to 50 parts surface-active agent, and about 4 to 94 parts solvent, all parts being by weight based on the total weight of the composition.
Application of the herbicide, antidote, or mixture thereof, can be carried out by conventional techniques utilizing, for example, hand-carried or tractor-mounted spreaders, power dusters, boom and hand sprayers, spray duster, and granular applicators. If desired, application of the compositions of the invention to plants can be accomplished by incorporating the compositions in the soil or other media.
The crop may be protected by treating the crop seed with an effective amount of antidote prior to planting. Generally, smaller amounts of antidote are required to treat such seeds. A weight ratio of as little as 0.6 parts of antidote per 1000 parts of seed may be effective. The amount of antidote utilized in treating the seed may be increased if desired. Generally, however, a weight ratio of antidote-to-seed weight may range from 0.1 to 10.0 parts of antidote per 1000 parts of seed. Since only a very small amount of active antidote is usually required for the seed treatment, the compound preferably is formulated as an organic solution, powder, emulsifiable concentrate, water solution, or flowable formulation, which can be diluted with water by the seed treater for use in seed treating apparatus. Under certain conditions, it may be desirable to dissolve the antidote in an organic solvent or carrier for use as a seed treatment of the pure compound alone may be used under properly controlled conditions.
For antidote seed-coating or for antidotes applied to soil in granular or liquid formulations, suitable carriers may be either solids, such as talc, sand, clay, diatomaceous earth, sawdust, calcium carbonate, and the like, or liquids, such as water, kerosene, acetone, benzene, toluene, xylene, and the like, in which the active antidote may be either dissolved or dispersed. Emulsifying agents are used to achieve a suitable emulsion if two immiscible liquids are used as a carrier. Wetting agents may also be used to aid in dispersing the active antidote in liquids used as a carrier in which the antidote is not completely soluble. Emulsifying agents and wetting agents are sold under numerous tradenames and trademarks and may be either pure compounds, mixtures of compounds of the same general groups, or they may be mixtures of compounds of different classes. Typical satisfactory surface active agents which may be used are alkali metal higher-alkylarylsulfonates such as sodium dodecylbenzenesulfonate and the sodium salts of alkylnaphthalenesulfonic acids, fatty alcohol sulfates such as the sodium salts of monoesters of sulfuric acid with n-aliphatic alcohols containing 8-18 carbon atoms, long-chain quaternary ammonium compounds, sodium salts of petroleum-derived alkylsulfonic acids, polyethylene sorbitan monooleate, alkylaryl polyether alcohols, water-soluble lignin sulfonate salts, alkali casein compositions, long-chain alcohols usually containing 10-18 carbon atoms, and condensation products of ethylene oxide with fatty acids, alkylphenols, and mercaptans.
Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. Various equivalents, changes, and modifications may be made without departing form the spirit and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.
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The disclosure herein relates to a new family of haloalkyl oxazolidinyl derivatives as antidotal compounds to reduce injury to crop plants by a variety of herbicides. The antidotal compounds are characterized particularly by having heterocyclyl or spiroheterocyclyl radicals attached to the 5-position of haloalkyl oxazolidine compounds and are especially useful as in-can antidotes against injury by acetanilide and thiocarbamate herbicides to corn, sorghum, soybeans, wheat, rice and other crops.
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BACKGROUND OF THE INVENTION
1. Field Of The Invention
The present invention relates to industrial equipment repair tools. More specifically, the present invention relates to tools for reshaping elevator buckets which have been distorted by normal use.
2. Description Of The Prior Art
A series of elevator buckets attached around the periphery of an endless conveyor belt is a commonly used apparatus for movement of loose, particulate matter such as gravel, bark or sawdust. Often, the movement course of such buckets is arranged whereby the buckets dig into a mound of the material to be moved. When working with raw, natural materials of the class described, inevitably an object will be encountered that damages one or more buckets by drawing and stretching the bucket lip to the extent that it will not pick up and hold the intended quantity of material.
Regardless of whatever removable fastener type is used to attach such buckets to the carrier belt, the fastener usually becomes damaged in normal use to such a degree as to make disassembly of the fastener difficult if not impossible. Since a plurality of fasteners are used depending on the size of the bucket, it is not unusual for at least one fastener of the plurality for each bucket to require removal by drilling, sawing or burning.
Moreover, it is often as economical to replace a damaged bucket with a new one since the heavy gauge material from which the buckets are made is usually stretched to a degree which necessitates heating and forging. It is for this reason that prior art implements such as that disclosed by C. F. Porter in his U.S. Pat. No. 1,620,920 is of little use on larger, heavy gauge buckets. While the Porter implement will correct diagonal racking of a bucket, it provides no correction of a stretched scraper or drag lip.
Additional prior art that may be relevant to the present invention is found in U.S. Pat. Nos. 2,010,713, 2,750,983 and 3,543,561.
What is desired, therefore, is a means whereby such buckets may be inexpensively reformed to a reasonably correct shape. Preferably, the desired means should perform the objective while the bucket remains mounted on the carrier belt thereby obviating the necessity to remove damaged fasteners.
SUMMARY OF THE INVENTION
This and other objects of the invention as perceived by those of ordinary skill are accomplished by a relatively light linear motor such as a portable hydraulic or screw jack connected between respective press platens. The press assembly is built about an elongated, rigid load carrying member characterized herein as a press bracket that is pivotally attached to a base platen at one end thereof and provides a seat base for the linear motor at the other end.
The base platen is secured tightly, as by two or more of the plurality of belt fasteners, to the damaged bucket along the inside face of the bucket mounting lip opposite from the drag lip. The press bracket extends over the bucket drag lip with the motor platen applied to the outside face of the drag lip adjacent to the press bracket.
A confining yoke is then clamped to the bucket drag lip on both lateral sides of the motor platen.
When the motor is extended, the force thereof is reacted against the bucket mounting lip to press the drag lip into proper alignment. Motor force misalignment which would otherwise cause the press bracket to expand away from the drag lip is resisted by the confining yoke.
BRIEF DESCRIPTION OF THE DRAWING
Relative to the drawing wherein like reference characters designate like or similar elements:
FIG. 1 is perspective illustration of a section of elevator bucket belt showing a mounted bucket of the type to which the utility of the present invention is directed;
FIG. 2 is an orthographic projection of the present invention in operative assembled position on a bucket;
FIG. 3 is a perspective illustration of the confining yoke positioned over a section of the press bracket with the motor platen guided therebeneath;
FIG. 4 is a sectionalized perspective of the base platen showing a portion of the bracket axle and one shaping bar.
FIG. 5 is an orthographic plan projection, of the present invention positioned for the first step of the reformation process.
DESCRIPTION OF THE PREFERRED EMBODIMENT
With reference to FIG. 1 for orientation, bucket belt elevators essentially comprise an endless course of heavy, but stiffly flexible belting 10 to which a multiplicity of buckets 12 are secured thereabout. The belt course is directed through the bed of particulate material that is to be moved so that the drag lip 13 of the bucket cuts into the material bed.
Usually, such buckets are mounted to the belting by means of countersunk, flathead machine screws 14 inserted from the power transmission face 15 side of the belt. Consequently, the threaded shank and nut for the screw fasteners 14 project into the bucket interior through the bucket side wall 16 opposite from the drag lip 13.
As the bucket is used, it encounters objects and conditions which exceed the strength of the bucket material thereby causing a sharp distortion generally following that of the dashed outline 17. The net effect of such distortion is to draw the bucket ends 18 in at the drag lip corners and to draw the drag lip 13 out at the center between the ends.
The base platen structure 20 for attaching the present invention to a selected, misshapen bucket pursuant to reformation is illustrated by FIGS. 2 and 4 and comprises a base plate 21 having counterbored apertures 22 drilled in a pattern to match that of bucket mounting fasteners 14. The counterboring of these apertures 22 is of such depth and diameter as to permit the base plate 21 to be positioned flush with the bucket mounting side wall 16 without removal of any particular fastener 14 nut. Consequently, damaged fasteners may be left undisturbed as the platen is secured in position by the projection of those remaining fasteners 14 having undamaged threads.
Upstanding normally from the base plate 21 ends are a pair of axle mounts 23 drilled to receive an axle shaft 24.
Pivotally mounted at the axle shaft 24 center is one distal end of the press bracket 27 which may be conveniently fabricated from a length of structural channel. At the opposite distal end of the press bracket is a motor base plate 28 having a socket pin 29.
Although not illustrated, the bracket 27 may be of greater, continuous length and the motor base plate 28 may be of the sliding adjustability type that wedges to a desired position under cantilevered load.
The linear motor 30 may be of any suitable type such as a screw jack or hydraulic pressure extended piston and cylinder, the latter type being illlustrated by FIG. 2. To the motor ram 31 end is secured the motor platen 32 having a pair of alignment tabs 33.
Dimensionally, the straight line axis between the axle shaft 24 and the motor socket 29 should align as nearly as convenient with the force axis 34 of the motor 30.
To resist any unbalancing couple remaining in the set-up, a bracket confining yoke 40 is clamped, by means of machine screws 41, to the drag lip 13 with yoke legs 42 positioned on opposite sides of the motor platen 32. The yoke bight 43 spans between the clamped legs 42 to prevent rising of the press bracket 27 away from the drag lip 13 edge when the motor ram 31 is extended.
To prevent collapse of a bucket by excessively extending a motor ram 31, a pair of shaping bars 44 are pivoted at one end from the axle shaft 24 so as to flank the confining yoke legs 42. A glide extension 45 from the shaping bar free end is long enough to abut the bucket drag lip 13 in the distorted condition and thereby maintain correct positionment of the abutment face 46 throughout the restoration stroke of the motor ram 31.
In operation, a distorted bucket 12 is first reformed longitudinally as FIG. 5 illustrates by fitting the motor cylinder base with a platen 35 similar to the motor platen 32 on the ram 31. When extended, the motor 30 will expand the bucket ends 18 to a flush, squared position with the platen faces: which is the desired shape. However, even when the ends 18 are restored to square, due to stretching of the drag lip 13, considerable distortion therein will remain. For this purpose, the apparatus of FIG. 2 is used.
To restore the drag lip 13, two or more undamaged bucket mounting fasteners 14 are selected to secure the base platen 20 to the bucket side wall 16. There is no requirement to remove the bucket from the belt 10.
With the base platen 20 in place, the press bracket 27 is positioned against the drag lip 13 and the confining yoke 40 positioned as shown and clamped by machine screws 41.
With the motor 30 in the collapsed condition, the motor platen 32 is positioned against the outside face of the drag lip 13 with the alignment tabs 33 resting against the edge. The motor 30 is then expanded until the cylinder base may be socketed over the pin 29.
Shaping bars 44 are then rotated into position with the glide extensions 45 resting against the drag lip 13 edge.
In this condition, the tool is completely aligned for final expansion of the motor 30 until the inner face of the drag lip 13 engages the shaping bar abutment faces 46 whereupon the bucket 12 shape is restored for use.
Having fully and completely described our invention,
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Misshapen elevator lift buckets are reformed without removal from the carrier belt by means of a linear motor socketed on a press bracket that is pivotally secured to the bucket mounting fasteners. Upon expansion of the linear motor, a distorted bucket drag lip is pressed back to substantially correct position.
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FIELD OF THE INVENTION
[0001] The present invention relates, generally, to robot operation and training. More specifically, various embodiments relate to the acquisition, organization, and use of task-related information by industrial robots to facilitate performance of tasks in an autonomous manner.
BACKGROUND OF THE INVENTION
[0002] Industrial robots perform a variety of tasks involving the movement and manipulation of physical objects. A typical industrial robot may, for example, have one or more arms, equipped with grippers, that allow the robot to pick up objects at a particular location, transport them to a destination location, and put them down in accordance with particular coordinates, thereby, for example, stacking them or placing them into cardboard boxes present at the destination location.
[0003] Robots may manipulate different types of objects and perform many tasks beyond simply moving them—for example, welding, joining, applying fasteners, etc. As a result, many different “end effectors” have been developed for deployment on robot appendages; some of these end effectors, such as grippers, have utility across a range of tasks, while others, such as weld guns, are designed to perform a single, specialized task. To promote versatility, a commercial robot may accommodate different end effectors. For example, different end effectors may share a common linkage design that permits them to be interchangeably mounted to the cuff or wrist of a robot arm. Accommodating the robot to the end effector operationally is more difficult. Frequently, selection of the end effector for a robot occurs during system integration or assembly and is essentially permanent; the programming necessary to operate the selected end effector is written into the controller code for the robot. In some robots, end effectors may be changed dynamically during operation, but typically this occurs at preprogrammed phases of task execution; that is, the robot controller code signals the need for a new end effector when the code governing the next task expects a replacement. Even dynamic changes in the robot's end effector, in other words, occur in response to robot expectation as it executes tasks or when the robot is outfitted for a new task.
[0004] What is needed, therefore, is a more versatile approach to hot-swapping of end effectors that permits arbitrary replacement by the operator and dynamic accommodation by the robot. The operator, for example, may find during operation that the task being performed by the robot unexpectedly requires finer control than the current set of grippers permits. In such circumstances, the operator will want to replace the existing grippers with a more suitable end effector, but without rewriting the robot's task-execution code.
SUMMARY OF THE INVENTION
[0005] The present invention relates to robots capable of accommodating dynamic replacement of end effectors, and hardware and software associated with the end effectors that facilitate communication with the robot to dynamically load and run software that allows the end effector to be operated without change to the main control program. Such effector-specific programming is herein generically referred to as a “driver.” The driver may be dynamically linked and run during program execution when the corresponding end effector is detected. Typically, the robot controller will store a library of drivers, and load the appropriate driver when a new end effector is detected; this process is referred to herein as “self-configuration.” The controller code itself, however, may issue generic commands not tied to any particular driver but to which appropriate drivers are coded to respond. This avoids the need to make changes at the controller-code level to accommodate different end effectors.
[0006] The term “configuration data” or “configuration information” refers to information identifying or helping to instantiate (e.g., select and parameterize) the proper driver for a particular end effector. Thus, configuration data may be an actual driver, parameters used to tailor a generic driver to a particular end effector, or merely an identifier for the type of driver needed. The term “identifier” or “identification data” refers to information that identifies the end effector and that may be combined with or used to locate appropriate configuration information for the end effector. As explained below, drivers, configuration data and identifiers can be variously distributed among components of a system depending on design priorities and preferences.
[0007] In various embodiments, the end effector is not connected directly to the robot appendage but instead to a “tool plate” that is removably mounted to the distal end of the robot appendage. The tool plate receives the end effector mechanically and may supply power and, in some cases, data signals thereto. Various types and degrees of functionality can be distributed between the end effector and the tool plate, and the latter may accommodate more than one type of end effector. This arrangement facilitates flexible deployment of capabilities as best suited to a particular robot architecture; for example, one component may be “dumb” (e.g., incapable of communication or data processing) and the other “smart” (e.g., capable of communicating with the robot and performing data-processing operations). Thus, one implementation features a “dumb” end effector and a “smart” tool plate. The smart tool plate may detect which of multiple types of connectable end effectors has been attached to it (e.g., based on electrical characteristics or the mechanical configuration of the end effector's connector), reporting this to the robot controller, which loads the appropriate driver. Alternatively, the smart tool plate may accommodate only a single type of end effector, in which case it need only report its own identity to the robot controller, since this is sufficient to determine the proper driver.
[0008] Another implementation features a “smart” end effector and a “dumb” tool plate, in which case the tool plate merely facilitates communication between the end effector's on-board processor or controller and the robot controller; the end effector reports its identity in a wired or wireless fashion to the robot controller. In this configuration, the tool plate may, for example, serve as an adapter between the robot appendage and a mechanically incompatible end effector. As explained below, “reporting” may be active (the “smart” component may initiate communication with the robot controller on its own and send information) or passive (the “smart” component may respond to a polling signal or other communication from the robot controller, which has detected attachment).
[0009] Accordingly, in a first aspect, the invention relates to a robot system with replaceable end effectors. In various embodiments, the robot system includes a robot body; a robot arm connected to the robot body and having a distal end including a first connector; a robot controller for controlling the robot arm and an end effector connected thereto; an end-effector removably connectable to the robot arm, where the end-effector assembly includes (1) an end effector; (2) nonvolatile memory storing data comprising identification information and/or configuration information; (3) a communication interface; (4) a processor; and (5) a second connector removably but securely matable with the first connector for establishing bidirectional communication between the processor and the robot controller via the communication interface. The processor is configured to cause transmission of the data to the robot controller upon mating of the first and second connectors, and the robot controller is adapted to self-configure based on the data and to control movements of the connected end effector based on the self-configuration.
[0010] In various embodiments, the first connector is disposed in a tool plate that is itself disposed at the distal end of the robot arm and removably connected thereto. The end effector is connected to the opposite side of the tool plate. The tool plate includes the nonvolatile memory, the processor and the communication interface. In some implementations, the tool plate is adapted to mate with a single type of end effector and stores the identification and/or configuration information relating thereto. In other implementations, the tool plate may accommodate multiple types of end effectors and store identification and/or configuration information for each end-effector type. Mating of the end effector to the tool plate establishes the end-effector type either mechanically or by means of data exchange. The tool plate, in turn, communicates with the robot controller to provide the identification and/or configuration information thereto.
[0011] As noted, the robot controller self-configures based on the deployed end effector. In some embodiments, the end-effector assembly supplies both identification and configuration information, e.g., a driver that the controller programming uses to operate the end effector. In other embodiments, the end-effector assembly supplies only identification information, and the controller locates the appropriate driver. For example, the controller (or other robot component) may store a series of drivers and a database relating end effectors to corresponding drivers. Once the controller learns the identity of the end effector, it selects and loads the appropriate driver based on the database entry corresponding to the identified end effector (without change to the main control program). If the controller is unable to locate a suitable driver, it may seek the driver remotely, either by communicating with a server acting as a master repository of drivers for end effectors, or by autonomously conducting an Internet search for suitable drivers and, if one is found, downloading and installing it.
[0012] In another aspect, the invention again relates to a robot system with replaceable end effectors. In various embodiments, the robot system includes a robot body; a robot arm connected to the robot body and having a distal end including a first connector; a robot controller for controlling the robot arm and an end effector connected thereto via the first connector; a tool plate removably connectable to the robot arm; and an end effector connected to the tool plate, where the tool plate includes (1) nonvolatile memory storing data comprising at least one of identification information or configuration information; (2) a communication interface; (3) a processor; and (4) a second connector matable with the first connector for establishing bidirectional communication between the processor and the robot controller via the communication interface. The processor is configured to cause transmission of the data to the robot controller upon mating of the first and second connectors, and the robot controller is adapted to self-configure based on the data and to control movements of the connected end effector based on the self-configuration.
[0013] In some embodiments, the data includes both identification information and configuration information. In other embodiments, the data does not include configuration information, and the robot system further comprises a database including records relating end-effector identification information to configuration information for the end effector. The controller is further adapted to query the database using the identification information to obtain the corresponding configuration information and to self-configure based thereon.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The foregoing will be more readily understood from the following detailed description of the invention, in particular, when taken in conjunction with the drawings, in which:
[0015] FIG. 1A is a perspective view of a robot in accordance with various embodiments.
[0016] FIG. 1B schematically illustrates internal and external components of the robot shown in FIG. 1A .
[0017] FIGS. 2A and 2B are perspective views of a tool plate in accordance with embodiments of the invention.
[0018] FIGS. 3A and 3B are perspective and plan views, respectively, that show the manner in which a tool plate in accordance herewith may mate with the end of a robot arm.
[0019] FIG. 4 schematically depicts an interoperating system including a robot arm, a tool plate, and a pair of end effectors in accordance with embodiments hereof
DETAILED DESCRIPTION
[0020] Refer first to FIGS. 1A and 1B , which illustrate, respectively, a perspective view of a representative robot 100 and a schematic detailing the various internal operative components. The robot 100 includes at least one robot arm 105 —as shown in FIG. 1B , a robot may have more than one arm—that terminates in one or more end effectors 110 for manipulating objects. The arm 105 has several (e.g., seven) degrees of freedom provided by suitable (and conventional) rotational joints. Each joint desirably employs a series elastic actuator, enabling the robot to sense external forces applied to it, such as, e.g., forces resulting from unexpected collisions. In the embodiment illustrated in FIG. 1A , a parallel-jaw gripper 110 that allows the robot to grasp, lift, and move objects is mounted at the end of the arm 105 ; as explained below, the gripper 110 is just one of many possible end effectors. The robot 100 also has a head-like screen 112 , which may display a pair of eyes or other output reinforcing the robot's orientation to nearby personnel or announcing its state. In some embodiments, the screen 110 can rotate about a vertical access, and nod about a horizontal axis running parallel to the long axis of the screen 110 .
[0021] The robot 100 includes one or more cameras 115 . In FIG. 1A , a camera 115 is shown above the screen 112 . The robot 100 may also include one or more range sensors in the wrist 117 of the appendage 105 , and in some embodiments, one or more sonar sensors detects moving objects in the environment. In addition to these sensors for visually and/or acoustically detecting objects, the robot 100 may include a number of touch-sensitive sensors and mechanical features on the arm 105 that facilitate mechanical interaction with a person (e.g., a trainer). For example, the robot 100 may include a set 118 of knobs and buttons (a “navigator”) that allows the user to respond to information displayed on the screen 112 (e.g., by selecting menu items, switching between training and execution mode) and enter numbers (e.g., to indicate in how many rows and columns objects are to be packed in a box) or text (e.g., passwords or object and task names) via a digital rotary knob.
[0022] The robot 100 described above is, of course, only one of many possible robot embodiments in accordance with the invention, and the various features described above are representative rather than limiting. Various components and features can be modified in manners that will be readily apparent to persons of skill in the art. For example, the robot may, generally, have any number of arms (or, more generally, appendages), and each arm may have any number of degrees of freedom. The links of the arms need not be joined by rotational joints with one degree of freedom (such as, e.g., hinge joints), but may, for example, include ball-and-socket joints that provide two rotational degrees of freedom, or rail systems that facilitate translational motion.
[0023] Robot operation is governed by a robot controller 125 , which monitors and alters robot positions, kinematics, dynamics, and forces; controls joint-level actuators to move the robot and/or its moving parts as directed by the robot controller; and high-level computational functionality that facilitates image-processing, user interaction, etc. The robot controller 125 may generally be implemented in hardware, software, or a combination of both on a general-purpose or special-purpose computer, which includes a bidirectional system bus 128 over which the central processing unit (CPU) 130 , memory 133 , and storage devices 136 communicate with each other as well as with internal or external input/output devices such as the screen 112 , the camera 115 , navigators 118 , wrist cuffs, and any other input devices and/or external sensors. A conventional communication interface 138 facilitates communications over a network, such as the Internet and/or any other land-based or wireless telecommunications network or system. The storage devices 136 store an end-effector database 140 which, as explained in greater detail below, maintains information relevant to the various types of end effectors 110 that may be associated with the robot 100 . The various modules may be programmed in any suitable programming language, including, without limitation, high-level languages such as C, C++, C#, Ada, Basic, Cobra, Fortran, Java, Lisp, Perl, Python, Ruby, or Object Pascal, or low-level assembly languages. The robot controller 125 may be implemented in software, hardware, or a combination.
[0024] The end effector 110 is connected to the robot arm 105 via a tool plate 150 , which may accommodate more than one type of end effector 110 and, in some implementations, more than one end effector at a time. In this way, the tool plate 150 acts as a “universal” connector that is mechanically and electrically connected to the robot 100 via the robot arm 105 , and which receives mechanical and electrical connectors from the end effector 110 . In addition, the tool plate 150 assists the robot controller 125 in locating and installing the appropriate driver for a particular end effector 110 . In various embodiments, the tool plate 150 may alert the robot controller when an end effector has been removed and replaced with a different (but compatible) end effector, providing information that allows the controller 125 to locate, load, and run the appropriate new driver in real time. The tool plate 150 may be one of several differently configured tool plates, each having identical mechanical and electrical connectors for mating with the robot arm 105 but different receptacles for receiving different end effectors. In this way, it is possible to accommodate more end effectors than the number of receptacles a single tool plate could physically support, and also facilitates system extensibility: as new end effectors with different connector configurations are developed, it is not necessary to replace the entire robot 100 or even the robot arm 105 ; rather, the ability to swap tool plates 150 means it is only necessary to design a new tool plate. Features of the tool plate 150 described below provide flexibility in this regard.
[0025] FIGS. 2A and 2B illustrate both faces of a representative tool plate 150 , and FIGS. 3A and 3B depict its attachment to the end of a robot arm. The face 205 includes a recess 210 having a circular perimeter and, at the center of the recess 210 , a raised platform 215 within which are 10 spring-loaded pins (pogo pins) 220 for establishing removable electrical connection to complementary receptacles. A plurality of bores 225 extend through the tool plate 150 and allow bolts to be passed through for secure attachment to the robot arm. In the illustrated embodiment, the effector-facing face 230 includes a raised annular ridge 235 with indentations 240 exposing the bores 225 . In some embodiments, these indentations 240 interlock with complementary extensions into the annular recess on the end effector (not shown) that receives the ridge 235 . A series of bolt holes 245 along the top surface of the ridge 235 allow the end effector to be secured to the tool plate 150 . In the illustrated embodiment, attachment of an end effector to the face 230 results only in a mechanical connection. Electrical signals and power are delivered to the mounted end effector by a pair of electrical connectors (e.g., M8 industrial connectors), which are connected via suitable cables to the end effector. As explained in detail below, the electrical signals and power typically originate with the robot controller and are received by the tool plate 150 via the pin connectors 220 . The tool plate 150 may include circuitry that converts signals and/or power received from the robot into a different form for the end effector mounted thereto.
[0026] With reference to FIGS. 2A and 3A , the tool plate 150 is brought into contact with the end face 305 of the robot arm 105 , and the raised annular ridge 310 on the end face 305 is received within the complementary recess 210 of the tool plate 150 . A series of bolt holes 315 align with the bores 225 through the tool plate, allowing the tool plate 150 to be bolted or otherwise mechanically secured to the robot arm 105 ; in some embodiments, however, a quick-release latch is used instead of bolts. The pin connectors 220 are received in a receptacle 320 as the tool plate 150 and the robot arm 105 assume the mated configuration illustrated in FIG. 3B .
[0027] The operation and key internal components of the tool plate 150 are illustrated in FIG. 4 . The tool plate includes a memory 405 , support circuitry 410 , and a control element 415 that may be a microprocessor, microcontroller, or other suitable component. The capabilities of the control element 415 depend on the functions assigned to the tool plate 150 , as described below. The tool plate mechanically and electrically mates with one or more end effectors 420 , two of which are representatively shown at 420 1 , 420 2 ; that is, the tool plate 150 has two receptacles, one for each of the end effectors 420 , and each containing appropriate features to facilitate mechanical and electrical mating therewith. As noted above, the tool plate 150 may simultaneously accommodate more than one end effector 420 and/or may interchangeably accommodate different types of end effectors. For example, instead of grippers with fingers that close around an object as shown in FIG. 1 , an end effector 420 may include suction grippers or other means of holding or manipulating an object. Alternatively or additionally, the end effector may be a tool (such as a drill, saw, welder, etc.), a measuring device (such as e.g., a scale, gauge, etc.) or other function-implementing device.
[0028] When mated mechanically and electrically with the robot arm 105 , the tool plate 150 receives power and establishes communication with the robot controller 125 (see FIG. 1B ). Typically, this occurs via intermediary hardware such as an interface 425 and a local motor controller 430 . The interface supplies power from the robot to the tool plate 150 and supports bidirectional data communication with the tool plate 150 via, for example, the RS-485 serial communication protocol; the support circuitry 410 of the tool plate 150 contains complementary communication components. The local motor controller 430 receives commands from the robot controller 125 (via, for example, a link-layer protocol such as Ethernet) and actuates motors associated with one or more nearby joints of the robot arm 105 to effect the commands. In the illustrated implementation, the local controller 430 also receives commands from the robot controller 125 that operate the end effectors 420 . It communicates these commands to the tool plate 150 via the interface 425 (using RS-485, for example), and the tool plate 150 issues commands (or provides power) to the addressed end effector via the Digital Out line. The commands are typically low-level commands specific to the end effector. That is, although the tool plate 150 could be configured to accept high-level, generic commands from the robot controller 125 and translate these into effector-specific signals, usually this is not done; rather, in more typical implementations, the robot controller 125 has “self-configured” to deliver effector-specific commands. The manner in which this may be accomplished is explained below. It should also be emphasized that the robot arm 105 may itself include a processor that can perform higher-level tasks. Thus, while the processor 415 may act as a “master” to control communications with the robot arm 125 , it may instead act as a “slave” to a processor in the robot arm (which may, for example, poll the tool plate 150 and transmit data to the robot controller).
[0029] When an end effector 420 is mated with the tool plate 150 , various communications take place whose end result is to provide power to and enable communication between the robot controller 125 and the end effector 420 , but also to enable the robot controller to self-configure in order to operate the end effector. In one representative implementation, the end effector is a “dumb” device with no onboard information to offer the robot controller. The tool plate 150 recognizes the end effector because of the receptacle configuration (e.g., it is designed to accept a single type of end effector), or from its mechanical and/or electrical characteristics, or because the tool plate accommodates only one type of end effector. In the illustrated embodiment, the memory 405 stores an identifier for each of the two possible end effectors 420 1 , 420 2 . When the control element 415 detects attachment of a particular end effector, it communicates the corresponding identifier to the robot controller 125 via the robot arm 105 . The robot controller uses the communicated identifier to locate, in the database 140 (see FIG. 1B ), configuration information for the end effector. The database 140 may contain a library of configuration information (e.g., drivers or pointers to drivers stored elsewhere), and upon selection of the driver information based on the received end-effector identifier, the robot controller 125 self-configures, i.e., loads and installs the proper driver. Because the tool plate 150 can detect both installation and removal of an end effector, these may be “hot swapped” in real time without powering down and re-booting the robot; via the circuitry 410 , the control element 415 will alert the robot controller 125 that a new end effector has been attached, and provide the identifier for the new end effector.
[0030] Detecting attachment of an end effector, either by the tool plate 150 or by the robot controller 125 (if, for example, the end effector is attached directly to a robot arm 105 ), can occur in an active or passive fashion. For example, the end effector or tool plate can initiate communication with the robot controller or the tool plate. Alternatively, the end effector or tool plate can, upon attachment, emit a characteristic signal that is detected by the robot controller polling for that signal. In either case, the robot controller 125 (or, in some implementations, the robot arm 105 ) sends commands to the end effector or the tool plate, which responds with data (I/O or status data, or stored configuration/identification data, depending on the command).
[0031] In some embodiments, the configuration information is stored in the memory 405 of the tool plate 150 , and upon detecting attachment of an end effector, the control element 415 locates the corresponding configuration information in the memory 405 and transmits this to the robot controller 125 . Once again, the configuration information may be the driver itself or a pointer thereto, enabling the robot controller 125 to download the latest version of the driver before self-configuring, or information that enables the robot controller 125 to parameterize a generic driver for the particular end effector. The memory 405 can also store end-effector-specific metrics such as cycle counts and hours of operation, allowing for preventive maintenance such as replacing suction cups when they are near their rated cycle limit.
[0032] In various implementations, any of the receptacles 420 can accommodate more than one type of end effector. In such cases, the end effector may store an identifier that is provided to (or retrieved by) the tool plate 150 upon establishing communication with a newly installed end effector. In this case, the tool plate 150 communicates the identifier to the robot controller 125 or, in some embodiments, uses the identifier to retrieve configuration information from the memory 405 and sends this information to the robot controller 125 . The optimal distribution of information—i.e., whether to store configuration information on the tool plate 150 or in nonvolatile memory on the robot itself—represents a design choice. The more information that is stored on the tool plate 150 , the more generic the robot can be, but the more memory the tool plate 150 will require. Another consideration is the need to update information or programming. For example, if the configuration data is subject to change over time, it may be desirable to store only unchanging information, such as an end-effector identifier, in the memory 405 ; the robot controller 125 can verify, at power-up or when installation of a new robot arm is detected, that it has the most current driver. It is possible, of course, to include functionality on the tool plate 150 enabling it to check for updates to stored configuration information before providing it to the robot, but such capability requires either on-board connectivity or the ability to access the network resources (e.g., via the Internet) through the robot.
[0033] In cases where the end effector is “smart,” i.e., contains its own configuration information, this can be retrieved by the tool plate 150 and provided to the robot controller 125 . It is even possible for the tool plate 150 to communicate wirelessly with end effectors and/or the robot controller 125 using a suitable on-board wireless interface. If, on the other hand, the robot controller 125 is unable to locate a suitable driver, it may search for a driver in a remote (e.g., hosted) repository of drivers or may autonomously conduct an Internet search for the proper driver, installing and testing proper operation and functionality via the tool plate 150 before actually allowing the robot to operate normally.
[0034] As previously noted, the control element 415 of the tool plate 150 may be any suitable microprocessor or microcontroller, depending on the functions that the tool plate is to perform. For example, the control element 415 may be a programmable microcontroller designed expressly for embedded operation, or one or more conventional processors such as the Pentium or Celeron family of processors manufactured by Intel Corporation of Santa Clara, Calif. The memory 405 may store programs and/or data relating to the operations described above. The memory 405 may include random access memory (RAM), read only memory (ROM), and/or FLASH memory residing on commonly available hardware such as one or more application specific integrated circuits (ASIC), field programmable gate arrays (FPGA), electrically erasable programmable read-only memories (EEPROM), programmable read-only memories (PROM), or programmable logic devices (PLD).
[0035] The terms and expressions employed herein are used as terms and expressions of description and not of limitation, and there is no intention, in the use of such terms and expressions, of excluding any equivalents of the features shown and described or portions thereof. In addition, having described certain embodiments of the invention, it will be apparent to those of ordinary skill in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the invention. In particular, embodiments of the invention need not include all of the features or have all of the advantages described herein. Rather, they may possess any subset or combination of features and advantages. Accordingly, the described embodiments are to be considered in all respects as only illustrative and not restrictive.
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Robots capable of accommodating dynamic replacement of end effectors load and run software that allows the end effector to be operated without change to the main control program. The driver may be dynamically linked and run during program execution when the corresponding end effector is detected. Typically, the robot controller will store a library of drivers, and load the appropriate driver when a new end effector is detected.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to grab bar assemblies; and, more particularly, to a grab bar assembly attachable to the side of a tub, such as a bathtub, for providing a support for assistance in entering and exiting the tub.
2. Description of the Prior Art
Grab bars are known in the art which are mounted to the side wall of a tub to assist a user to get into and out of the tub. However, all tubs are not alike and have side walls, to which such bars are usually secured, of varying curvatures. Thus, grab bars for such tubs, for example, spas, jacuzzis, bathtubs, etc., must be individually manufactured to provide the proper mounting for the particular side wall curvature of the tub to which the grab bar is to be mounted.
There thus exists a need for a universal adjustable grab bar assembly which can be mounted to any surface yet provide the proper spacing between the grab bar and the mounting surface for grasping the same.
SUMMARY OF THE INVENTION
It is an object of this invention to provide an adjustable universal grab bar assembly for a tub or the like which can be mounted to any desired surface.
It is a further object of this invention to provide an adjustable universal grab bar assembly which can be mounted to any adjacent surfaces to provide a spaced bar which can be grasped by a user to assist the user in supporting him or herself.
These and other objects are preferably accomplished by providing a bar assembly including a bar having a relatively straight central portion and angled ends. The ends rotate within end holders bolted or otherwise secured to the wall of a tub or the like. The configuration of the end holders, and the angularity of the angled ends, is such that the grab bar assembly may be mounted to irregularly shaped surfaces, such as curved, angled, etc., yet provide a suitable space between the bar and the surface to enable a user to grasp the same.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a top plan partly sectional view of a grab bar assembly mounted to a mounting surface;
FIG. 2 is a plan view of the grab bar alone of the assembly of FIG. 1;
FIG. 3 is a view taken along lines 3--3 of FIG. 2;
FIG. 4 is a vertical cross-sectional view of one of the end holders of the assembly of FIG. 1 with the washer of FIG. 1 installed thereon;
FIG. 5 is a view taken along lines 5--5 of FIG. 4;
FIG. 6 is a front vertical view of the holder of FIGS. 4 and 5;
FIG. 7 is a top plan view of the washer alone of FIG. 1;
FIG. 8 is a view taken along lines 8--8 of FIG. 7; and
FIGS. 9 to 11 are illustrative views of the mounting of the assembly of FIGS. 1 to 8 to various surfaces.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to FIG. 1 of the drawing, a grab bar assembly 10 is shown mounted to the side wall 11 of a tub or the like. Grab bar assembly 10 includes an elongated grab bar 12 having a generally straight midportion 13 (see also FIG. 2) with downwardly angled ends 14, 15 interconnected by elbow portions 16, 17, respectively. Midportion 13 may be about 5.875" in overall length with ends 14, 15 about 1.75" in overall length.
As seen in FIG. 2, line 18, at the intersection of end 14 and portion 16 and perpendicular to the central longitudinal axis of end 14, may make an angle a of about 22°30' with line 19, at the intersection of portion 16 and midportion 13 and perpendicular to the central longitudinal axis of midportion 13. Line 18 may make a radius of curvature of about 3" from its intersection with line 19 to bar 12. The angularity of end 15, portion 17, and midportion 13 may be identical.
As seen in FIG. 3, bar 12 may be hollow having an outer diameter of about 1 inch and a wall thickness of about 32 thousandths of an inch.
The ends 14, 15 are receivable in end holders 20, 21, respectively. End holders 20, 21 are identical and, thus, end holder 20 in FIG. 4 may have an outer peripheral wall 22 comprised of spaced generally straight front and rear walls 23, 24 (FIG. 5) interconnected by curved end walls 25, 26, respectively (the points of connection being curved as seen in FIG. 5). As seen in FIG. 4, inner wall 27 is spaced from outer wall 22, the thickness thereof being about 0.125". As seen in FIG. 6, side 22 may slope inwardly at an angle of about 1° to the vertical.
Looking again at FIG. 4, inner wall 27 extends first generally vertically upwardly to upper inner annular lower partition wall 28 which, at the front (to the right in FIG. 4), curves downwardly. Wall 28 surrounds a boss 29 having a tapped throughbore 30. The bottom annular wall 32 of boss 29 lies in a horizontal plane spaced from the horizontal plane of the bottom annular wall 33 of holder 20 (e.g., a distance of about 0.062 inches). Also, the peripheral side wall 34 of boss 29 may taper downwardly and inwardly toward the central axis thereof, e.g., about 2° with respect to the vertical.
Wall 22 at the rear of holder 20 extends upwardly to a top wall 35 (domed or arced at top as seen in FIG. 6) and rounded at a radius of about 1/16 of an inch. Top wall 35 is spaced from upper partition wall 36 which, together with annular lower partition wall 28, forms a partition wall 37.
Walls 35, 36 form an opening at the front (or right side in FIG. 4) of holder 20 which opening is closed off at the rear by a slanted rear wall 38. Walls 35, 36 and 28 thus provide a socket 39 for receiving end 14 therein, as will be discussed. As seen in FIG. 6, socket 39 is at least slightly greater in its smallest diameter than the outer diameter of bar 12, e.g., at least 5/1000ths of an inch greater.
Although any suitable dimensions may be used, in conformity to the dimensions heretofore given for grab bar 12, holder 20 may be about 1.749 inches long (from front to rear) and about 1.25 inches wide. The distance from the bottom wall 33, as indicated by line 40, to a horizontal line 41 intersecting with both the plane of the opening of socket 39 (indicated by line 57) and the central longitudinal axis 42 of socket 39 (at the front or right side in FIG. 4) may be about 1.422". This angle of intersection b may be about 22°30'. As heretofore mentioned, the inner smaller diameter of socket 39 may be about 1.005 inches. This allows free rotation of bar 12 in holders 20, 21. The outer diameter of holder 20 (between the outside of top wall 35 and the outside of wall 37 (at the front end or right side in FIG. 4) may be about 1.25".
The length of wall 35 may be about 1.375" (to its intersection with wall 22). All edges may be rounded, as shown at 35'. As seen in FIG. 5, holder 20 may be slightly wider at the front end (right side in FIG. 5) than at the rear end (left side in FIG. 5) thereof (e.g., varying from a width of about 1.299 inches at the front to about 1.281 inches at the rear). The semi-elliptical side 26 blends with flat sides 23, 24 to the smaller semi-elliptical side 25. These sides 25, 26 are based on two 22°30' semi-ellipses, the left side 25 being smaller than the right end 26. Boss 29 may be about 1/2" in outer diameter with a 1/4" tapped hole therethrough.
Any suitable materials may be used, such as brass alloy. The brass alloy may have a smooth outer finish for plating purposes and, thus, may be plated with polished chrome or any other suitable finish such as antique brass. Of course, the dimensions will vary depending on tolerances, plating, finishing, etc.
Although the 1.005 inches inner diameter of inclined socket 39 is preferred, this too can vary. However, it must be of sufficient diameter to receive therein end 14 (which, as heretofore mentioned, may be one inch in diameter).
Bar 12 (and thus ends 14, 15) may also be of brass alloy and may also be chrome plated or finished in any other suitable manner, such as antique brass. Ends 14, 15 must slide into sockets 39 in an easy sliding fit with minimum looseness.
As seen in FIG. 1, a washer 43 (see also FIGS. 7 and 8) is provided between each holder 20, 21 and side 11. As seen in FIG. 7, washer 43 is similarly configured to the bottom plan view of holder 20, as seen in FIG. 5. Thus, each washer 43 has a right end semi-elliptical side wall 44 blending into straight side walls 45, 46 which then blend into left end semi-elliptical side 47. Each end 44, 47 is again based on two 22°30' ellipses and washer 43 may be about 1.789" long and about 1.299" wide (at end 44) and about 1.281" wide (at end 47). A hole 48, about 0.265" in diameter, is provided through washer 43. As seen in FIG. 8, washer 43 is about 0.125" in thickness and is comprised of a lower section defined by flange 49 which is wider than an upper section (defined by peripheral wall 50--see also FIG. 7). Flange 49 may be about 0.062" thick and the distance x in FIG. 8 may be about 0.531".
Washer 43 may be of any suitable material, such as rubber, soft vinyl or any suitable plastic. It should be of a material sufficient to resist deterioration when submerged in water. The outer flange 49 will be under compression in use and washer 43 must be flexible and of a medium hardness.
Referring once again to FIG. 4, washer 43 is placed over the bottom of each holder, such as holder 20. The reduced diameter portion of washer 43, defined by wall 50, enters into the interior of holder 20 and abuts against the bottom wall 32 of boss 29. Hole 48 aligns with hole 30. The thickness of the reduced diameter portion of washer 43, defined by wall 50, is related to the distance between wall 32 of boss 29 and bottom wall 33. Thus, the outer diameter of wall 50 is generally related to the inner diameter of wall 27 and conforms thereto. The outer diameter of flange 49 conforms to the outer configuration and diameter of outer wall 22.
The means for mounting each holder 20, 21 to the application, such as side wall 11, will obviously depend upon the installation and access to the blind side of the wall 11.
In operation, each holder 20, 21 is slid onto the ends 14, 15 of grab bar 12 and are free to rotate 360°. Two identical shaped washers 43 are now mounted onto the bottom of each holder 20, 21, as heretofore discussed, and act as interface cushioning means between holders 20, 21 and the installation (such as wall 11). The holders 20, 21 are now mounted to the installation, such as wall 11, as heretofore discussed.
As seen in FIG. 4, a screw 54 is threaded through wall 11 and then threaded into tapped throughbore 30 in each holder 20, 21. The tip 55 of screw 54 digs into the end 14 forming a dimple 56 therein which serves to retain bar 12 in non-rotating position in holders 20, 21 (of course, after rotating bar 12 to the desired position for the application as will further be discussed).
FIG. 1 illustrates the bar assembly 10 mounted to a flat surface. In FIG. 9, bar 12 has been rotated slightly in holders 20, 21 allowing the holders 20, 21 to be mounted to a sharply curved wall 51. As can be seen, the bottom flat surface 33 of each holder conforms as much as possible to the plane of the curved contacting surface which is accomplished by rotation of bar 12. In FIGS. 9-11, the washers 43 have been omitted for convenience of illustration. The bar assembly 10 can thus be mounted to a curved surface, the orientation of the bar 12 varying depending upon the place of mating between surface 43 (or surfaces 33 if washer 43 is eliminated) and the installation wall.
As seen in FIGS. 10 and 11, the assembly 10 can even be mounted between two flat surfaces 52, 53, making an angle of 90°. As seen in FIG. 10, bar 12 is oriented such that ends 14, 15 extend away from the surfaces 52, 53 directly opposite the assembly in FIG. 1 where ends 14, 15 extend toward surface 11. In FIG. 11, one end 14 may extend inwardly and one end may extend away. These adaptations of assembly 10 to such surfaces is accomplished by rotation of bar 12, or one or both ends 14, 15, or a combination of rotation of bar 12 and one or both of ends 14, 15.
Thus, FIG. 10 shows bar 12 mounted against an inside 90° corner such as typically found in a rectangular shower. The two end holders 20, 21 have been rotated 180° each from the position shown in FIG. 1. Bar 12 is installed generally parallel to the floor with the ends 14, 15 set at the same distance from the corner.
In FIG. 11, bar 12 is asymmetrically disposed across the same 90° corner as in FIG. 10, but in a randomly selected position. Thus, using the unique geometry of the angled ends of bar 12, and the identical angle of the sockets 39 in each holder 20, 21 relative to a horizontal datum plane indicated by line 41 in FIG. 4, the bar 12 can be mounted to a variety of straight, curved and angled surfaces. That is, by combining the rotational characteristics between bar 12 and holders 20, 21, bar 12 can be mounted to a great number of concave, curved, warped, flat and angled surfaces (of course, angled surfaces less than 180°).
As heretofore noted, bar 12 and holders 20, 21 may be of any suitable materials. For example, a spacing of 11/2" between bar 12 and the mounting surface is preferred. Although a 1" outer diameter bar 12 has been discussed as preferred, obviously bar 12 (and, of course, socket 39) can take other dimensions, such as an O.D. for bar 12 of about 11/4" to 11/2".
The angle of 22°30' for ends 14, 15 and holders 20, 21 may, of course, vary but is preferred for most efficiently carrying out the teachings of the invention. Bar assembly 10 may have a variety of applications, but primarily may be used to assist one in getting in and out of a tub, spa, bath, etc.
Although a particular mechanical connection of holders 20, 21 to the mounting surface or wall 11 in FIG. 1 has been disclosed, obviously holders 20, 21 may be secured to the mounting surface in any suitable manner, such as by use of suitable adhesives. In the invention disclosed herein, if a 250# load is placed on bar 12 at the middle portion 13 thereof, it will not rotate beyond 1/16th of 360°.
Washer 43 allows a flush fit of the holders 20, 21 and the screw 54, forming a dimple 56 in ends 14, 15, providing an interlock between bar 12 and holders 20, 21, preventing rotation after installation. Washer 43, in addition to providing an interface for a flush fit between the holders 20, 21, which may be metallic, cushions the edges of the holders 20, 21 with respect to side wall 11 (or any other installation surface).
Brass is preferred because it is platable, ductile and non-corroding. Dimple 56 can be formed in a hollow brass tube, as bar 12, without rupturing.
There is thus disclosed a grab bar assembly which can be quickly and easily assembled to any surface or mating surfaces at an angle of 180° or less.
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An adjustable and universal grab bar assembly for a tub or the like. The bar assembly includes a bar having a relatively straight central portion and angled ends. The ends rotate within end holders bolted or otherwise secured to the wall of a tub or the like. The configuration of the end holders, and the angularity of the angled ends, is such that the grab bar assembly may be mounted to irregularly shaped surfaces, such as curved, angled, etc., yet provide a suitable space between the bar and the surface to enable a user to grasp the same.
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BACKGROUND OF THE INVENTION
[0001] This application relates to shoe soles, and in particular to a plastic shoe sole having fabric applied thereto.
[0002] Typically, a shoe includes an outsole and a shoe upper or vamp secured to the outsole. The outsole of the shoe is an exposed portion of the shoe which makes contact with the ground. For this reason, the outsole is designed and manufactured with various performance characteristics, such as, traction, stability, and wear resistance. Economic factors also affect the design and manufacture of shoe outsoles. The economics of shoe manufacturing can be affected by placing fabric on the bottom surface of the outsole.
SUMMARY OF THE INVENTION
[0003] Briefly stated, a method is provided for gluing a fabric insert to the bottom surface of a shoe outsole. In particular, the shoe outsole is formed with a recess which receives the fabric insert. A groove or channel can extend around the recess to facilitate hiding of the edge of the fabric insert to prevent fraying of the fabric and to form a clean edge to the fabric insert. Raised tread forming members can be provided which extend from the recess. The tread forming members can, for example, be ribs which extend from the recess. In this instance, the fabric insert will have slots or openings through which the tread forming members extend. Tread surfaces can also be provided by printing a tread pattern on the fabric insert.
[0004] The method for producing the outsole includes preparing the outsole for glue by removing oils and particles from the outsole recess. For example, the recess can be wiped with methyl ethyl ketone. The recess is then primed by coating the recess with a polyurethane cement primer. Lastly, a glue, such as a polyurethane cement is applied over the primer. Polyurethane cement is also applied to one surface of the fabric insert. The fabric insert is pressed into the recess so that the polyurethane cement applied to the fabric insert contacts and binds with the polyurethane cement in the shoe recess. The outsole and the fabric insert can be dried between steps.
DESCRIPTION OF THE DRAWINGS
[0005] In the accompanying drawings which form part of the specification:
[0006] FIG. 1 is a bottom view of an outsole according to the present invention;
[0007] FIG. 2 is an enlarged sectional view of the outsole along A-A of FIG. 1 ; and
[0008] FIG. 3 is a flow chart showing the steps of making the outsole of FIG. 1 .
[0009] Corresponding reference numerals indicate corresponding parts throughout the several figures of the drawings.
DETAILED DESCRIPTION
[0010] The following detailed description illustrates the invention by way of example and not by way of limitation. The description clearly enables one skilled in the art to make and use the invention, describes several embodiments, adaptations, variations, alternatives, and uses of the invention, including what is presently believed to be the best mode of carrying out the invention. Additionally, it is to be understood that the invention is not limited in its application to the details of construction and the arrangements of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.
[0011] A shoe outsole 10 includes a bottom surface 12 having a recess 14 formed therein. The recess 14 receives a fabric insert 16 . A groove or channel 17 extends around the periphery of the recess 14 . Raised tread members 18 can extend from the recess 14 to protrude slightly beyond the outer, bottom, surface of the fabric insert. Tread members can be formed in other ways as well. For example, a rubber or plastic tread pattern can be printed on the fabric insert 16 . If raised tread members 18 are used, the fabric insert 16 includes slots or openings through which the tread members 18 protrude. These slots or openings will correspond in shape to the raised tread member so that the edge of the slot or opening will be adjacent the sides of the raised tread member. In the embodiment of FIG. 1 , four rib-shaped raised tread members 18 are shown. They are about ¼″ wide and of different lengths between about 1½″ to about 3″ and extend lengthwise relative to the recess 14 . However, those skilled in the art will recognize that other shapes, sizes, and arrangements of raised tread members 18 can be used.
[0012] The outsole 10 is preferably made from thermoplastic rubber (TPR) or poly vinyl chloride (PVC), but other plastic materials known to those skilled in the art can also be used. The fabric insert 16 can be any desired woven or non-woven material that will withstand the expected wear.
[0013] The fabric insert 16 is secured or fixed in the recess 14 of the outsole 10 by a gluing process, as described below. First, a solution of methyl ethyl ketone (MEK) is applied to a contact surface 24 of the recess 14 with a brush, roller, spray, or other appropriate means to remove any surface oils from the recess contact surface 24 . The outsole 10 is then allowed to dry. The drying of the outsole can be expedited, for example, by placing it into a drying apparatus at about 60° C. for approximately three (3) minutes.
[0014] After drying of the outsole, a primer is applied to the contact surface 24 with a brush, roller, spray, or other appropriate means. In the preferred embodiment, the primer is a mixture of chlorinated solvent and polyurethane cement having 2% Desmodur®, a brand name for a group of isocyanates and isocyanate prepolymers for urethane adhesives available from Bayer Aktiengesellschaft. The chlorinated solvent effectively opens pores of the contact surface 24 , which receive the cement. This allows for the glue (i.e., cement) in the primer to penetrate the outsole to form a better connection between the glue and the outsole, and ultimately to form a better bonding of the fabric insert 16 to the outsole 10 . The outsole 10 is again dried. As noted above, drying can be accomplished by placing the outsole into the drying apparatus at about 60° C. for approximately four (4) minutes.
[0015] Next, one or more coats of polyurethane cement having 2% Desmodur®, are applied to the primer with a brush, roller, spray, or other appropriate means. The outsole 10 is again allowed to dry. Drying can be expedited by placing the outsole into the drying apparatus at about 60° C. for approximately six (6) minutes.
[0016] One or more coats of polyurethane cement having 2% Desmodur® are also applied to a surface 36 of the fabric insert 16 with a brush, roller, spray, or other appropriate means. The fabric insert 16 is dried, for example, by placing it into the drying apparatus at about 60° C. for approximately six (6) minutes. The polyurethane cement can be applied to the fabric insert 16 at any desired time relative to the processing of the outsole.
[0017] Once the glue has been applied to the outsole 10 and fabric insert 16 , the fabric insert can be fixed (i.e., glued) to the outsole 10 . This is accomplished by placing the fabric insert 16 into the outsole recess 14 so that cement coated side of the fabric insert 16 contacts the cement coated contact surface 24 of the outsole recess. Initially, the fabric insert 16 is attached to the outsole 10 by pressing the fabric softly into the recess 14 , for example, by hand. The outsole 10 with fabric insert 16 then is placed into a pressing machine that mechanically presses against the outsole 10 and fabric insert 16 for approximately 8-10 seconds. Sufficient pressure is applied by the press to insure proper bonding between the entire surface of the fabric insert 16 and outsole 10 . Preferably, a polyurethane or silicone pad is adjacent to the fabric insert 16 during pressing. The pad is a mold that is of the same shape of the finished sole. The pad will urge the edge of the fabric insert 16 into the groove 17 about the periphery of the recess 14 to provide a clean or neat edge to the fabric and to reduce the possibility of the fabric fraying.
[0018] In the preparation process, the glue (i.e., the polyurethane cement) at least partially impregnates the fabric insert. As noted above, the glue also penetrates the pores that are opened or formed by the primer. As is apparent, the glue applied to the fabric insert is the same glue that is applied to the outsole. Hence, when the two glue coated surfaces are brought into contact, and the glue is activated under pressure, the glue of the fabric insert will bond with the glue of the outsole to thereby form a single contiguous layer or coating of glue between the outsole and the fabric insert. Thus, on one side, this glue layer will be penetrated into the outsole pores, and on the other side, the glue layer will be impregnated into the fabric insert. This will form strong connection to permanently affix the fabric insert 16 into the outsole recess 14 .
[0019] Changes can be made in the above constructions without departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense. For example, different chemicals can be used to clean the surface of the recess. As can be appreciated, what is important is that the surface be cleaned to accept and adhere to the glue. An alternate glue can be used. Something other than the chlorinated solvent or isocyanate can be used to prime the recess to form or open the pores in the recess 14 . These examples are merely illustrative.
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An outsole for a shoe has a bottom surface with a fabric insert glued into a recess. The method of gluing the fabric insert to the shoe outsole comprises cleaning the recess of the outsole, priming the recess to receive glue, applying glue to the recess; applying glue to the fabric insert; and pressing the fabric insert into the recess to fix the fabric insert in the recess.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No. 13/993,320 filed 2 Jul. 2013, which application is a US National Stage of International Application No. PCT/GB2011/052457, filed 12 Dec. 2011, which application claims the benefit of GB 1021267.8, filed 15 Dec. 2010, all herein fully incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of Invention
[0003] The present invention is directed to a pharmaceutical composition in the form of a spray/aerosol which can be used to deliver unpalatable compounds, such as NSAIDs. In particular, the present invention is directed to a flurbiprofen-based spray.
[0004] 2. Background and Related Art
[0005] Flurbiprofen is a member of the phenylalkanoic acid derivative family of non-steroidal anti-inflammatory drugs (NSAIDs) used to treat inflammation and pain. It is predominately used in the treatment of rheumatoid arthritis due to its anti-inflammatory effect.
[0006] Flurbiprofen is very insoluble in low pH aqueous solution, and its solubility increases slightly as the pH increases. Flurbiprofen has varying solubility in different organic solvents. Different formats and applications of flurbiprofen have been developed, such as flurbiprofen lozenges used in the treatment of sore throats. Mouthwashes containing flurbiprofen have also been developed; as well as mouth sprays that deliver a low (<0.5% w/v) level of the active
[0007] Flurbiprofen is known for producing a burning sensation in the buccal cavity (the mouth). This flurbiprofen related burn is extremely unpleasant causing an irritating prickly sensation at the back of the throat as well as a cough, gag, tickle or irritation depending on its concentration. It is desirable to reduce this ‘burn’ in flurbiprofen-containing products, and there has been considerable effort in this area. For example, there has been much effort in developing flavors that mask the burn with various flavors. The absence of taste receptors at the back of the throat and the ineffectiveness of flavors to cover the burn appear to confirm that the issue to be addressed is the irritating effect of flurbiprofen on pain receptors at the back of the throat.
[0008] Cyclodextrins are a family of compounds which are saccharide polymers. These sugar derivatives are formed from differing numbers of sugars bound together to form a cyclic oligosaccharide. As can be seen below α-CD consists of 6 membered sugar ring while β-CD and γ-CD consist of a 7 and 8 membered sugar ring respectively. Cyclodextrins are produced from starch by means of enzymatic conversion. The cyclic structure provides the cyclodextrin molecule with a large surface area, and also allows other smaller molecules to enter it forming an inclusion complex; this provides endless potential uses for cyclodextrins.
[0009] The cyclodextrin's ability to form complexes by “encapsulating” other molecules has plenty of applications, such as in drug delivery systems.
[0010] Liquid compositions which comprise an NSAID and a cyclodextrin are known in the art. For example, WO 92/00725 discloses compositions which contain ketoprofen, a cyclodextrin and dimethyl isosorbide. The presence of the isosorbide provides the composition with anti-plaque properties and enhances the anti-inflammatory properties.
[0011] WO 95/04528 discloses powder compositions containing a complex of an NSAID and a cyclodextrin for re-formulation with water to form a drink. The composition requires the presence of an acid/base couple to ensure that the complex of NSAID and cyclodextrin dissolves. A similar composition is described in WO 95/07104.
[0012] U.S. Pat. No. 5,042,997 describes an ibuprofen-containing liquid. The compositions disclosed therein are not suitable for use in a spray format. A similar composition is described in WO 2005/079858.
[0013] EP 1 574 221 describes an injectable composition which comprises diclofenac. Similarly, WO 2009/089269 describes a method of treating pain in subjects with increased risk of significant blood loss. The compositions disclosed therein comprise diclofenac and a cyclodextrin, and are most suitable for injection.
[0014] EP 1 974 751 discloses a composition which comprise an NSAID, a cyclodextrin and an amine. The presence of the amine results in the formation of an amine salt which improves the solubility of the NSAID.
[0015] Yet, none of these prior art documents describes a composition which is suitable for use as a spray to treat sore throat.
[0016] Liquid compositions which comprise an NSAID and a cyclodextrin are known in the art. Typically, these compositions can be in the form of powders that require reconstitution to form a product in the form of a consumable drink or an injectable liquid. Prior art compositions can also include specific excipients which either enhance their anti-inflammatory effect or improve the solubility of the NSAID.
[0017] Yet, none of these prior art documents describes a composition which is suitable for use as a spray to treat sore throat.
BRIEF SUMMARY OF THE INVENTION
[0018] Briefly described, in a preferred form, the present invention provides a significantly higher concentration of NSAID per fluid volume than compositions that are currently available.
[0019] According to a first aspect of the present invention there is provided a liquid composition in comprising an aqueous solution of an NSAID and one or more cyclodextrins.
[0020] Typically the NSAID is selected from the group consisting of ibuprofen, ketoprofen, flurbiprofen, diclofenac, naproxen. Preferably the NSAID can be selected from ketoprofen or flurbiprofen. Most preferably the NSAID is flurbiprofen.
[0021] The cyclodextrin can be selected from α, β, γ cyclodextrin and derivatives thereof. Cyclodextrins for use in the present invention include the natural cyclodextrins and their derivatives, including the alkylated and hydroxyalkylated derivatives and the branched cyclodextrins. derivatives bearing sugar residues are of special interest. Especially useful herein are the hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of α, β, γ,-cyclodextrin. Specific cyclodextrin derivatives for use herein include methyl α cyclodextrin, hydroxyethyl α cyclodextrin, hydroxypropyl α cyclodextrin, dihydroxypropyl α cyclodextrin, methyl β cyclodextrin, hydroxyethyl β cyclodextrin, hydroxypropyl β cyclodextrin, dihydroxypropyl β cyclodextrin, methyl γ cyclodextrin, hydroxyethyl γ cyclodextrin, hydroxypropyl γ cyclodextrin and dihydroxypropyl γ cyclodextrin.
[0022] The ratio of the NSAID to cyclodextrin is between 1:0.5 and 1:1.5. The ratio can be between 1:0.7 and 1:1. A preferred ratio is 1:0.87. For the avoidance of doubt, the ratios for NSAID and cyclodextrin are molar ratios.
[0023] The composition comprises the NSAID at a level of at least 1% w/v. The composition can contain 1-5% w/v. The composition preferably contains no more than 3.2% NSAID. The composition can contain a most preferred amount of NSAID is 1.6% w/v. In an alternative embodiment the preferred amount is 3.13% NSAID.
[0024] Typically the composition contains a buffer. The term “buffer” refers to a pharmaceutically acceptable excipient that helps to maintain the pH of the solution within a particular range specific to the buffering system. The buffer is present for example at a concentration in the range from about 0.03% to about 5.0% w/v, or about 0.1% to about 2.0% w/v. Non-limiting illustrative examples of pharmaceutically acceptable buffering agents include phosphates, ascorbates, acetates, citrates, tartrates, lactates, succinates, amino acids and maleates. Particularly preferred buffers are disodium hydrogen orthophosphate, citric acid or combinations thereof.
[0025] The pH of a composition in preferred embodiments is generally from about 6 to about 9. Typically, the pH of the liquid formulation is about 7.4. Alternatively, the pH of the liquid formulation may be selected from the following ranges: 6.5 to 8.5; 7.0 to 8.0; and 7.2 to 7.6.
[0026] The composition can further contain a thickening agent such as hydroxy ethyl cellulose, hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose or hydroxy propyl cellulose.
[0027] Minor amounts of other ingredients such as pH adjusters (e.g., a base such as NaOH), emulsifiers or dispersing agents, preservatives, sweeteners, and flavorants may also be present.
[0028] A preferred composition according to the present invention comprises:
1-5% flurbiprofen; 5-10% one or more α, β, γ cyclodextrins and derivatives thereof; up to 5% one or more aqueous buffers; and 80-90% water.
[0033] The composition may further comprise up to 1% one or more flavorants, up to 0.2% sweetener and up to 0.5% preservatives.
[0034] The composition may further comprise up to 0.5% thickening agent.
[0035] The composition can be used in a spray format, or as part of a gargle or mouthwash. A preferred format is as a sprayable liquid.
[0036] The composition can be provided as a unit dose of up to about 2 ml. The composition can be provided as a unit dose of up to about 1 ml. The composition can be provided as a unit dose of up to about 0.5 ml. The composition can be provided as a unit dose of up to about 0.4 ml. The composition can be provided as a unit dose of up to about 0.3 ml. The composition can be provided as a unit dose of up to about 0.2 ml. The composition can be provided as a unit dose of up to about 0.1 ml.
[0037] A dose can comprise one or more sub-doses. Typically, the dose can comprise 1-5 sub-doses. The dose can comprise two or three sub-doses. By way of example, if the dose is 0.6 ml, then it can comprise 6×0.1 ml sub-doses, 4×0.15 ml sub-doses, 3×0.2 ml sub-doses, 2×0.3 ml sub-doses, or 1 ×0.6 ml dose.
[0038] In an exemplary embodiment, a dose comprises three sub-doses, being three sprays of 0.18 ml, to give a total of 0.54 ml.
[0039] According to another aspect of the present invention there is provided the use of a pharmaceutical composition as described in the first aspect of the invention for the treatment of sore throat.
[0040] According to another aspect of the present invention there is provided a method of treating a sore throat using a formulation as described in the first aspect of the invention.
[0041] According to another aspect of the present invention there is provided a method of reducing the irritation or burn associated with flurbiprofen comprising administering to an individual a composition in accordance with the first aspect of the present invention.
[0042] According to another aspect of the present invention there is provided a method of improving the stability of flurbiprofen when in solution wherein the solution includes compounds bearing a hydroxyl group which do not act as a solvent and wherein the method includes the step of mixing the flurbiprofen with a cyclodextrin prior to addition of the compounds bearing a hydroxyl group.
[0043] Typically the solution containing the flurbiprofen is an aqueous solution.
[0044] Typically the method is used to form a composition in accordance with the first aspect of the present invention.
[0045] These and other objects, features and advantages of the present invention will become more apparent upon reading the following specification in conjunction with the accompanying drawing figures.
BRIEF DESCRIPTION OF THE DRAWINGS
[0046] Embodiments of the present invention will be now described by way of example only with reference to the accompanying drawings in which:
[0047] FIG. 1 illustrates α, β, γ cyclodextrin;
[0048] FIG. 2 illustrates the minimum pH required to achieve solution clarity for different beta cyclodextrin:flurbiprofen ratios at a flurbiprofen concentration of 14.58 mg/ml;
[0049] FIG. 3 illustrates the minimum pH required to achieve solution clarity for different beta cyclodextrin:flurbiprofen ratios at a flurbiprofen concentration of 31.25 mg/ml;
[0050] FIG. 4 illustrates degradation studies on Example 4 of the present invention; and
[0051] FIG. 5 illustrates degradation studies on Example 5 of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0052] To facilitate an understanding of the principles and features of the various embodiments of the invention, various illustrative embodiments are explained below. Although exemplary embodiments of the invention are explained in detail, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the invention is limited in its scope to the details of construction and arrangement of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, in describing the exemplary embodiments, specific terminology will be resorted to for the sake of clarity.
[0053] It must also be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. For example, reference to a component is intended also to include composition of a plurality of components. References to a composition containing “a” constituent is intended to include other constituents in addition to the one named.
[0054] Also, in describing the exemplary embodiments, terminology will be resorted to for the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.
[0055] Ranges may be expressed herein as from “about” or “approximately” or “substantially” one particular value and/or to “about” or “approximately” or “substantially” another particular value. When such a range is expressed, other exemplary embodiments include from the one particular value and/or to the other particular value.
[0056] Similarly, as used herein, “substantially free” of something, or “substantially pure”, and like characterizations, can include both being “at least substantially free” of something, or “at least substantially pure”, and being “completely free” of something, or “completely pure”.
[0057] By “comprising” or “containing” or “including” is meant that at least the named compound, element, particle, or method step is present in the composition or article or method, but does not exclude the presence of other compounds, materials, particles, method steps, even if the other such compounds, material, particles, method steps have the same function as what is named.
[0058] It is also to be understood that the mention of one or more method steps does not preclude the presence of additional method steps or intervening method steps between those steps expressly identified. Similarly, it is also to be understood that the mention of one or more components in a composition does not preclude the presence of additional components than those expressly identified.
[0059] The materials described as making up the various elements of the invention are intended to be illustrative and not restrictive. Many suitable materials that would perform the same or a similar function as the materials described herein are intended to be embraced within the scope of the invention. Such other materials not described herein can include, but are not limited to, for example, materials that are developed after the time of the development of the invention.
[0060] As used herein, the term “consisting essentially of” means the composition contains the indicated components and may contain additional components provided that the additional components that are non-active and do not materially affect the composition's basic characteristics. As used herein, the term “consisting of” means the composition contains the only indicated components and excludes other components.
[0061] As used herein, the term “up to” means that the component is present in the composition to the level of the value given. For example, the term “up to 5%” would mean that a component is present at a level greater than 0% and less than or equal to about 5%.
Example 1
[0062] 1.683 g of flurbiprofen and 6.265 g of beta cyclodextrin (BCD) were weighed into a 100 ml volumetric flask. 50 ml of pH 7.4 buffer solution was added to the volumetric flask and shaken to suspend and wet the BCD and flurbiprofen. 1 M NaOH (aq) was added dropwise with vigorous stirring until the flurbiprofen and beta cyclodextrin dissolved fully. 6 ml of NaOH solution was required to dissolve the BCD and flurbiprofen. The solution was made up to 100 ml with purified water and mixed well. The solution was clear and colorless. The pH was measured and found to be pH 7.40 exactly.
[0063] Additional examples were prepared in a similar way. Details of these compositions are given below.
[0000]
Example 2
Example 3
Example 4
Example 5
Material Name
(% w/w)
(% w/w)
(% w/w)
(% w/w)
Flurbiprofen
1.62
1.62
1.62
1.62
Beta Cyclodextrin
6.04
6.04
4.228
4.228
Disodium Hydrogen
3.1825
3.1825
3.1825
3.1825
Orthophosphate
Citric Acid Monohydrate
0.11655
0.11655
0.11655
0.11655
Methyl
0.2187
0.2187
0.2187
0.2187
p-hydroxybenzoate
Propyl
0.04374
0.04374
0.04374
0.04374
p-hydroxybenzoate
Sodium Hydroxide
0.24
0.24
0.24
0.24
Mint Flavor
0.20
0.20
0.20
0.20
Cherry Flavor
0.25
0.25
0.25
0.25
Hydroxyethyl Cellulose
—
0.20
—
—
WS-23
—
—
0.10
0.10
Sodium Saccharin
0.05
0.05
0.05
0.05
Hydroxypropyl Beta
—
—
2.238
—
Cyclodextrin
Methyl Beta
—
—
—
2.24
Cyclodextrin
Purified Water
88.03851
87.83851
87.5125
87.51051
TOTAL
100.00
100.00
100.00
100.00
[0064] FIG. 2 illustrates the minimum pH required to achieve solution clarity for different beta cyclodextrin:flurbiprofen ratios and the effect of variation of the ratio of BCD to flurbiprofen on the minimum pH required as a result of gradual addition of 1M NaOH to obtain clarity. The required pH remains high until a ratio of about 0.75:1, at which point there is a dip in the threshold pH until the ratio is 1:1. The dip centers at a ratio of 0.87:1 BCD:Flurbiprofen. The flurbiprofen concentration is fixed at 8.75 mg per 600 μl.
[0065] FIG. 3 illustrates the change in minimum required pH observed at a higher concentration of flurbiprofen. The dip in threshold pH centers at BCD:Flurbiprofen ratios of 0.95:1 to 1.05:1.
[0066] FIGS. 4 and 5 illustrated the improved stability for the compositions of Examples 2 and 4 of the present invention. There is no significant degradation of flurbiprofen up to 52 weeks even at 40° C./75% RH. The results are given in the table below. Test compositions which contained ethanol showed degradation of between 10% and 14% within two weeks.
[0000]
Example 4
Example 2
Flurbiprofen
Flurbiprofen
Time
Content (%
Content (%
points
mg per ml)
mg per ml)
Storage
0
1.6788
1.6997
Conditions
25° C./60% RH
2
1.7014
1.6863
4
1.7029
1.6989
8
1.6456
1.7027
12
1.7011
1.7024
26
1.7142
1.6886
39
1.7365
1.7115
52
1.6832
1.6908
30° C./65% RH
2
1.6912
1.6939
4
1.6889
1.6941
8
1.6698
1.6622
12
1.6945
1.6979
26
1.7204
1.7117
39
1.6982
1.7115
52
1.6870
1.6922
40° C./75% RH
2
1.6798
1.7004
4
1.7028
1.6904
8
1.7022
1.7019
12
1.6992
1.7286
26
1.7030
1.7060
52
1.6845
1.6930
[0067] An advantage of the present invention is that there is provided a clear physically and chemically stable solution of flurbiprofen of sufficient concentration to be used in a throat spray product, where the clinically optimized dose of active pharmaceutical substance can be delivered/metered by a pump or other spray mechanism in a small volume of (concentrated) solution together with a method of preparation. Such a solution does not exhibit the undesirable taste associated with compositions that are at higher pH, i.e. above about pH 8.
[0068] A further advantage of the present invention is that there is avoided the use of an alcohol as a co-solvent thus resulting in a composition with improved stability. The presence of an alcohol in a composition containing an NSAID with a carboxylic acid moiety results in the production of the corresponding ester. The compositions of the present invention do exhibit unexpected stability in the presence of other hydroxyl-containing compounds that are not solvents. For example, the flavor system used in the example embodiments does not result in higher levels of degradation of the flurbiprofen.
[0069] Numerous characteristics and advantages have been set forth in the foregoing description, together with details of structure and function. While the invention has been disclosed in several forms, it will be apparent to those skilled in the art that many modifications, additions, and deletions, especially in matters of shape, size, and arrangement of parts, can be made therein without departing from the spirit and scope of the invention and its equivalents as set forth in the following claims. Therefore, other modifications or embodiments as may be suggested by the teachings herein are particularly reserved as they fall within the breadth and scope of the claims here appended.
|
A liquid throat spray composition for topical application to a sore throat including an aqueous solution of an NSAID and cyclodextrin.
| 0 |
TECHNICAL FIELD
At least one embodiment of the present invention provides centrifuge/magnet-based analyzers and methods of operating thereof. More particularly, the methods are related to manipulation of the centrifugal force and regional magnetic field on the centrifuge/magnet-based analyzers by changing the rotational speed.
DESCRIPTION OF THE RELATED ART
Enzyme-linked immunosorbent assay (ELISA) is an assay which has been widely used to determine the presence of specific proteins in biochemistry. Based on the specific binding between an antibody and its antigen and the following color development, ELISA can also be applied as quantitative assays for chemical and biological molecules.
In 1972, Peter Perlmann and Eva Engvall published the first method to perform ELISA, which is famous in its high sensitivity. ELISA is popular in laboratories, especially in clinical levels, and one of the most well-known ELISA techniques is the “sandwich” ELISA. In a sandwich ELISA, the primary antibodies, antigens, horseradish peroxidase (HRP) labeled secondary antibodies, and substrates will be sequentially added to perform the test.
Conventional methods usually use 96-well microtiter plates to perform ELISA. Since each step in ELISA requires some incubation time and washing procedure, running ELISA consumes a lot of time on operating equipment and waiting for reactions to complete. And this is more acute when running ELISA on 96-well microtiter plates, because each well in the 96-well microtiter plates needs to be handled individually. Another disadvantage of conventional methods is that manual operations (e.g., using micropipette to load and distribute reagents) would lead to human errors and fatally affect the results.
In a sandwich ELISA, the primary antibodies are coated on the plate in advance. This indirect method of ELISA would dampen the binding efficiency of antibodies and therefore require more reagents and reaction time to complete a test. A sandwich ELISA, from coating primary antibodies to completing the tests, usually takes hours to days to finish. Moreover, more reagents and reaction time indicates that more non-specific binding would be induced.
In order to improve the defects by using 96-well microtiter plates, compact disc (CD) ELISA, a new technique featured in combining ELISA and centrifugal force, has been proposed. CD ELISA is a technique based on centrifugal force and discs similar to compact discs to perform ELISA. The discs used in CD ELISA are also known as chips, because they are coated with antibodies or antigens on the matrix and etched with multiple micro-channels, chambers, and microvalves on the surface.
A microvalve can trap fluid while the rotational speed of the disc is below the microvalve's burst frequency. If liquid is under a centrifugal force, the centrifugal force applied on the liquid will drive the liquid to move. But if the liquid moves to a microvalve, the microvalve will induce capillary pressure on the liquid-air interfaces to counteract with the centrifugal force and resist the liquid from moving through. Based on the counteraction between the centrifugal force and the capillary pressure, the liquid is trapped and stops moving while that the centrifugal force is no more than the capillary pressure. However, if the rotational speed is accelerated and the centrifugal force applied on the liquid is increased, the balance between the centrifugal force and the capillary pressure will finally be broken and the liquid will eventually surge through the microvalve. The rotational speed which broke down the balance between the centrifugal force and the capillary pressure at a microvalve is the burst frequency of the microvalve.
Users can inject several reagents into chambers on a disc in advance, and release the reagents sequentially and separately during an assay by controlling the rotational speed of the disc. Under different rotational speeds, different reagents will be release into an incubation chamber for reactions. In addition, CD ELISA requires a small amount of reagents but provide a high contact area for reactions, the reaction rate therefore can be significantly increased. Based on these advantages, CD ELISA can automatically complete the processes in few hours.
However, few disadvantages of CD ELISA have been identified. One is that the microvalves used in conventional CD ELISA are unstable, and one is that antibodies are hard to be uniformly coated on such micro-scale solid supports.
Each microvalve used in conventional CD ELISA has a burst frequency. This is one of the bases to sequentially and separately release reagents by controlling rotational speed. However, the burst frequency of a microvalve is fixed to a rough range instead of one specific rotational speed. Liquid usually surmounts a microvalve when the rotational speed is falling within the +/−20% range of the said burst frequency. Accordingly, if the burst frequencies of any two microvalves are close and the ranges are partially overlapping, reagents designed to be sequentially released may surmount the microvalves simultaneously and lead to failures.
Furthermore, coating antibodies on the solid support and binding antigens to the antibodies on a disc is difficult and unstable if the disc is in millimeter scale. The inconsistent distribution of antibodies and antigens among chambers, or even within one single chamber, will largely affect the results.
Some solutions have been proposed to improve the stability of microvalves. One of the solutions is wax plug, which is made of paraffin wax with a low melting point. The wax plug is to replace the microvalve to block microchannels. If a liquid trapped by a wax plug is going to be released into downstream chambers, laser will irradiate on that wax plug to open the microchannel. The technique using laser-controlled wax plugs provides a sophisticated mechanism to manipulate the release sequence of reagents and avoids the leakage often happened in conventional microvalves. However, discs using laser-controlled wax plugs are far from affordable. The discs require precise instrument to be fabricated and work.
Some other solutions have been proposed to improve the efficiency of antibody coating. One of the solutions is microsphere, which is mostly made of plastic or magnetic materials. The microspheres are covered with functional groups for conjugating with antibodies or antigens. The conjugated microspheres will be injected into chambers to interact with samples and reagents in an assay. But how to retain the injected microspheres in a chamber is a problem.
Conventionally, microchannels in micrometer scale are used to trap plastic microspheres in a chamber since that the microchannels allow fluid, but plastic beads, to pass through. However, fabricating such fine microchannels is costly. Some others provide an alternate solution, which is utilizing magnetic beads and magnetic field. The movement of magnetic beads can be controlled by magnetic field generated from an external source. The magnetic field attracts and keeps the magnetic beads in a chamber during incubation and reactions. However, the magnetic field is invariable and the movement of magnetic beads is stagnant in this technique.
Since the magnetic field is constantly fixed at a place, the reaction between the antibodies and sample would be less effective. Furthermore, magnetic beads are still retained ineffectively under the magnetic field.
SUMMARY
At least one embodiment of the present invention provides a centrifuge/magnet-based analyzer. More particularly, the centrifuge/magnet-based analyzers alter the centrifugal force and regional magnetic fields by changing the rotational speed to move the magnetic beads.
At least one embodiment of the present invention provides a centrifuge/magnet-based analyzer. The centrifuge/magnet-based analyzer comprises a first disc. There are multiple first magnetic units disposed on the first disc, in which the multiple first magnetic units are located on the same radius ring or different radius rings centered on the center of the first disc.
The centrifuge/magnet-based analyzer also comprises a second disc, in which the second disc is the main disc to conduct analysis. The second disc is configured below and adjacent to the first disc, but not directly contact with or attached to the first disc. The second disc comprises a first air vent, a first main chamber, a second air vent, a second main chamber, a third air vent, a third main chamber, a first microvalve, a second microvalve, third microvalves, and multiple reaction units.
More particularly, the first air vent is disposed at the center of the second disc. The first air vent is connected to the first main chamber while the first main chamber is further connected to the second main chamber via the first microvalve. The second main chamber, on the other hand, comprises the second air vent. Similarly, a third main chamber comprising the third air vent is connected to the second main chamber via the second microvalve. The third main chamber is further connected to the multiple reaction units via the third microvalves.
Each of the multiple reaction units comprises an entry, an incubation chamber, a sample chamber, a detection chamber, a waste chamber, a fourth microvalve, and a forth air valve. The entry is connected to the third microvalve and the incubation chamber respectively, and the incubation chamber is separately connected with the sample chamber and the detection chamber. Notably, the sample chamber is configured at top side of the incubation chamber while the detection chamber is configured at the bottom side of the incubation chamber. The detection chamber is further connected with the waste chamber via the fourth microvalve and the air vent is connected to the top side of the waste chamber.
The centrifuge/magnet-based analyzer also comprises a third disc, in which the third disc is configured below and attached with the second disc. More particularly, the third disc comprises multiple tracks. Each track in the third disc contains a second magnetic unit, and the second magnetic unit is free to move in the track accommodating thereof.
At least one embodiment of the present invention provides a method of operating centrifuge/magnet-based analyzers. The method begins with an injecting step, an affixing step, and a configuring step. More particularly, at least one reagent, magnetic beads, and the sample are injected into a second disc in the injecting step and the second disc is affixed to a third disc in affixing step. The third disc here comprises multiple tracks, in which each track accommodates a second magnetic unit. Furthermore, the at least one reagent here can be any solution based on analysis requirements. After the affixing step, the second disc and the third disc together are configured to a first disc in the configuring step, in which the first disc comprises multiple magnetic units.
The method further comprises a rotating step, a releasing step, and an obtaining step. In the rotating step, the rotational speed of the second disc is elevated to an incubation speed to mix and incubate. In the following releasing step, the rotational speed of the second disc is increased to at least one release speed. More particularly, the number of the at least one release speed is determined in accordance with the number of the at least one reagent. The at least one release speed is to selectively and sequentially release the at least one reagent. In the obtaining step, optical analysis is applied to obtain results while the rotational speed of the second disc is at an analyzing speed.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates a centrifuge/magnet-based analyzer, according to some embodiments of the present invention.
FIG. 2 illustrates a second disc, according to some embodiments of the present invention.
FIG. 3 illustrates a reaction unit, according to some embodiments of the present invention.
FIG. 4 illustrates the configuration of first magnetic units on a first disc, according to some embodiments of the present invention.
FIG. 5 illustrates a third disc, according to some embodiments of the present invention.
FIGS. 6A-6E illustrate the motion of magnetic beads, according to some embodiments of the present invention.
FIG. 7 is a flow diagram illustrating a method of operating centrifuge/magnet-based analyzers, according to some embodiments of the present invention.
FIG. 8 is a graph illustrating the result of quantitative hCG testing performed with some embodiments of the present invention.
FIG. 9 is a graph illustrating the result of CA-125 level testing performed with some embodiments of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 illustrates a centrifuge/magnet-based analyzer, according to some embodiments of the present invention. As illustrated in FIG. 1 , the centrifuge/magnet-based analyzer comprises three layers. From the top to the bottom, the three layers are a first disc 11 , a second disc 12 , and a third disc 13 respectively. Before performing an assay, the second disc 12 and the third disc 13 are attached together by, for example, using a pair of male fasteners and female fasteners. The second disc 12 and the third disc 13 are then mounted onto a centrifuge, which is a place adjacent to the first disc 11 .
Referring to FIG. 2 and FIG. 3 , FIG. 2 illustrates a second disc and FIG. 3 illustrates a reaction unit, according to some embodiments of the present invention. As illustrated in FIG. 2 and FIG. 3 , a first air vent 122 is disposed at the center of the second disc 12 . The first air vent 122 is connected to the first main chamber 123 while the first main chamber 123 is further connected to the second main chamber 125 via a first microvalve 1231 . The second main chamber 125 , on the other hand, comprises the second air vent 124 . Similarly, a third main chamber 127 comprising a third air vent 126 is connected to the second main chamber 125 via the second microvalve 1251 . The third main chamber 127 is further connected to multiple reaction units 2 via the third microvalve 1271 .
In some embodiments, a first reagent, a second reagent, a third reagent are injected into the first main chamber 123 , the second main chamber 125 , and the third main chamber 126 respectively through the first air vent 122 , the second air vent 124 , and the third air vent 126 . That is, the first air vent 122 , the second air vent 124 , and the third air vent 126 are not only used for ventilation but also used as injection ports.
In FIG. 2 , the embodied disc comprises six reaction units 2 . However, the number of the reaction units 2 is not limited to six. The number of the reaction units 2 is determined based in part on the analysis requirements. For example, the disc could be designed as, similar to convention microtiter plates, containing twenty-four reaction units or ninety-eight reaction units, which the number is a multiple of six.
In FIG. 3 , the embodied reaction unit 2 is connecting with the third microvalve 1271 . More particularly, an entry 21 is connected to the third microvalve, and an incubation chamber 23 is connected to the entry 21 . The incubation chamber 23 is further connected with a sample chamber 22 and a detection chamber 24 separately. Notably, the sample chamber 22 is configured at top side of the incubation chamber 23 while the detection chamber 24 is configured at the bottom side of the incubation chamber 23 . Furthermore, the detection chamber 24 is connected with a waste chamber 25 via the fourth microvalve 251 and a forth air vent 252 is connected to the top side of the waste chamber 25 .
In some embodiments, the first microvalve 1231 , the second microvalve 1251 , the third microvalve 1271 , and the fourth microvalve 1291 each is a string of hollow spheres connected together. However, in accordance with the analysis requirement, the first microvalve 1231 , the second microvalve 1251 , the third microvalve 1271 each can also be a fishbone-shaped microvalve or a twisted microchannel.
FIG. 4 illustrates the configuration of first magnetic units on a first disc, according to some embodiments of the present invention. On the exemplary first disc 11 , four radius rings centered on the center of the first disc 11 were virtually drawn for further explanations. The four radius rings are in four different radii, in which the R 1 , R 2 , R 3 , and R 4 in FIG. 4 denote the four radii respectively. And multiple first magnetic units 111 are disposed on the four radius rings respectively to provide a control mechanism to control the magnetic beads 3 .
FIG. 5 illustrates a third disc, according to some embodiments of the present invention. As illustrated in FIG. 5 , the third disc 13 comprises multiple tracks 131 . The number of tracks in this exemplary third disc 13 is consistent with the number of reaction units in the exemplary first disc 11 in FIG. 2 . Each track 131 is in zigzag and contains a second magnetic unit 1311 , in which the second magnetic unit 1311 is free to move in the track 131 accommodating thereof. If the first disc 11 , the second disc 12 , and the third disc are configured together, the second magnetic units 1311 is able to move relatively to the first magnetic units 111 on the first disc 11 and affect the reaction in the reaction units 2 on the second disc 12 . The first magnetic unit and the second magnetic unit 1311 each can be an electromagnet or a permanent magnet. Since permanent magnets do not require energy to be active, the first magnetic units and the second magnetic units in some embodiments both are permanent magnets.
The mechanism underlying the centrifuge/magnet-based analyzers will be further explained in the following embodiments. The embodiments of FIGS. 6A-6E are focusing on reaction units 2 performing ELISA. However, the present invention may be applied to devices and fields other than ELISA in some other embodiments.
FIGS. 6A-6E illustrates the motion of magnetic beads, according to some embodiments of the present invention. FIG. 6A is a top view of the combination of the first disc 11 , the second disc 12 , and the third disc 13 . In particular, the second disc 12 is attached to the third disc 13 , and the second disc 12 and the third disc 13 together is placed adjacently to the first disc 11 . The sample chamber 22 is used as an injection port for samples and reagents of ELISA, e.g. primary antibodies and HRP labeled secondary antibodies. In the embodiments of FIG. 6A , the sample chamber 22 is used for injecting magnetic beads 3 coated with antibodies or antigens.
After the magnetic beads 3 , the sample, and the antibodies are injected, the second disc 12 will begins to spin to drive these fluid and magnetic beads 3 into a detection chamber 24 . As the second disc is continuing to spin, the magnetic beads will be attracted by second magnetic units 1311 in tracks 131 of the third disc 13 and shuttle between the detection chamber 24 and the incubation chamber 23 .
Since the second magnetic units 1311 are free to move, they will be attracted by the first magnetic beads 111 which are respectively located on the R 1 ring, the R 2 ring, the R 3 ring, and the R 4 ring on the first disc 11 . As illustrated in FIG. 6B-6E , the magnetic beads 3 will be attracted indirectly by the first magnetic units 111 on the R 1 ring, the R 2 ring, the R 3 ring, and the R 4 ring while the second disc 12 is rotating relatively to the first disc 11 .
In some late stages, the rotational speed of the second disc 12 will reach a threshold that the centrifugal force applied on the second magnetic units 1311 is greater than the magnetic force between the first magnetic units 111 and the second magnetic units 1311 . And the second magnetic units 1311 will be spun down and stay at the position as illustrated in FIG. 6A . At the same time, the magnetic beads, attracting by the second magnetic units 1311 , are kept in the detection chamber 24 instead of flowing into the waste chamber 25 .
The method of operating the centrifuge/magnet-based analyzers will be explained in the following embodiments.
FIG. 7 is a flow diagram illustrating a method of operating centrifuge/magnet-based analyzers, according to some embodiments of the present. As illustrated in FIG. 7 , the method is initiated with injecting at least one reagent, magnetic beads 3 , and at least one sample into a second disc 12 . The second disc 12 , then, is affixed to a third disc 13 . In particular, the third disc 13 comprises multiple tracks 131 and each track 131 accommodates a second magnetic unit 1311 .
The at least one reagent comprises a reagent I, a reagent II, and a reagent III in the embodiments. For ELISA, the reagent I here is the stop solution, the reagent II is the developing reagent, and the reagent III is the wash buffer.
In some embodiments, the reagent I (i.e., the stop solution) is injected into a first main chamber 123 through a first air vent 122 , the reagent II (i.e., the developing reagent) is injected into a second main chamber 125 through a second air vent 124 , and the reagent III (i.e., the wash buffer) is injected into a third main chamber 127 through a third air vent 126 . Moreover, magnetic beads 3 (i.e., magnetic beads 3 conjugated with primary antibody), the secondary antibody (i.e., the secondary antibody conjugated with HRP), and the sample are injected into an incubation chamber 23 through a sample chamber 22 .
As used in conventional ELISA, the wash buffer may be a PBS-T wash buffers comprising 0.05% Tween-20, and the developing reagent may be the substrates for the enzyme (e.g., the HRP enzyme) coupling with the primary antibody or even Coomassive Brillian Blues (e.g., Coomassie Brilliant Blue G-250). The stop solution may, depending on the assay, be strong acids (e.g., 2M H 2 SO 4 and HCl) or strong bases (e.g., NaOH).
In the following step, the second disc 12 , along with the third disc 13 , is configured to a first disc 11 , in which the first disc 11 comprises multiple first magnetic units 111 . In particular, the second disc 12 and the third disc 13 is configured below the first disc 111 to induce the magnetic attraction between the second magnetic units 1311 in the third disc 13 and the first magnetic units 111 in the first disc 11 . The distance between the first disc 11 and the second/third discs 12 , 13 will determine the strength of the magnetic attraction, a user thus can adjust the distance between the discs in accordance with rotational speed used in an assay.
After the discs are configured together, the second disc 12 will be rotated at a spread speed, the first rotational speed, to spread the reagent I, the reagent II, the reagent III, the magnetic beads 3 , the secondary antibody, and the sample. More particularly, the spread speed is under the burst frequencies of the first microvalve 1231 , the second microvalve 1251 , and the third microvalve 1271 . Therefore, the reagent I, the reagent II, and the reagent III is spreading within the main chambers respectively during this stage. And the sample, the magnetic beads 3 , and the secondary antibody are spreading into the incubation chamber 23 and the detection chamber 24 .
After these elements for ELISA have been spread in the chambers respectively, the second disc 12 will be rotated at an incubation speed, the second rotational speed. Under the incubation speed, the magnetic attraction between the first magnetic units 111 and the second magnetic units 1311 is greater than the centrifugal force applied on the second magnetic units 1311 . Because second magnetic units 1311 are relatively rotating to the first magnetic units 111 , the second magnetic units 1311 will be attracted by different first magnetic units 111 and shuttle in the tracks 131 like illustrated in FIG. 6B-6E .
After the incubation stage, the second disc 12 will be rotated at at least one release speed. The number of the at least one release speed may be in accordance with the number of the at least one reagents. Therefore, the rotational speed of the second disc 12 will be increase from one level to another to selectively release some reagents in the disc, until all the reagent were released.
In the embodiments of FIG. 7 , the reagent III is the first to release to perform the washing step, as in conventional ELISA. The rotational speed of the second disc 12 is first elevated to a level that the centrifugal force applied on the second magnetic units 1311 is greater than the magnetic force. Under this stage, the second magnetic units 1311 will be spun down to the end of the tracks 131 , a distal region from the center of the third disc 13 . At the same time, the magnetic beads 3 are attracted and kept in the detection chamber 24 of the reaction unit 2 of the second disc 12 , whereas the reagents and sample are flowing into a waste chamber 25 of the reaction unit 2 of the second disc 12 .
After that, the second disc 12 will be rotated at one of the at least one release speed. At this rotational speed, the centrifugal force applied on the second magnetic units 1311 is greater than the magnetic force, and most the antibodies and the sample will be in the waste chamber 25 . Besides, the reagent III in the third main chamber 127 will surmount the third microvalve 1271 and flow into the detection chamber 24 of the reaction unit 2 to perform the washing step.
After the washing step, the second disc 12 will be further rotated at another of the at least one release speed. At this rotational speed, the centrifugal force applied on the second magnetic units 1311 is greater than the magnetic force, and the reagent III will flow into the waste chamber 25 . Besides, the reagent II in the second main chamber 125 will surmount the second microvalve 1251 and the third microvalve 1271 and flow into the detection chamber 24 of the reaction unit 2 to develop colors.
Similar to the incubating step, the developing step may also utilize the magnetic beads 3 to facilitate the reaction. The second disc 12 will be rotated at a developing speed, which is another rotational speed. Under the developing speed, the magnetic attraction between the first magnetic units 131 and the second magnetic units 1311 is, again, greater than the centrifugal force applied on the second magnetic units 1311 . And the second magnetic units 1311 will attract the magnetic beads 3 to shuttle between the incubation chamber 23 and the detection chamber 24 to facilitate the color development.
After the developing step, the second disc 12 will be rotated at still another of the at least one release speed. At this rotational speed, the centrifugal force applied on the second magnetic units 1311 is greater than the magnetic force, and the reagent I in the first main chamber 123 will surmount the first microvalve 1231 , the second microvalve 1251 , and the third microvalve 1271 and flow into the detection chamber 24 of the reaction unit 2 to inactive reactions and generate end products.
In the embodiments of FIG. 7 , the release speeds for the reagent I, the reagent II, and the reagent III are different, and each is greater than another. That is, the release speed for the reagent I is greater than that of the reagent II, while the release speed for the reagent II is greater than that of the reagent III.
In the analyzing step, the second disc 12 will be rotated at an analysis speed, which is yet another rotational speed, while under the detection of a spectrophotometer. The spectrophotometer is used to obtain the optical density of each end product.
The embodiments of FIG. 7 are used to explain the underlying mechanism of the centrifuge/magnet-based analyzers. Though the following embodiments are also based on ELISA and the second disc 12 and the third disc 13 in FIG. 7 are collectively referred to as the “combined discs” therein, it should be obvious that the application of the centrifuge/magnet-based analyzers is not limit to ELISA.
The first experiment was conducted to determine the concentration of human chorionic gonadotropin (hCG) in samples. Similar to FIG. 7 , the magnetic beads 3 conjugated with the primary antibody, the secondary antibody, and six samples were injected into the sample chamber 22 . The six samples are products of a serial dilution, which is originated from a known source. The concentration of each sample is listed in Table 1.
TABLE 1
Sample
Sample
Sample
Sample
Sample
Sample
A
B
C
D
E
F
hCG
0
10
20
50
100
250
(mIU/mL)
In particular, the volume of the magnetic beads 3 is 15 μL and the secondary antibody is 20 μL. Furthermore, 120 μL of the stop solution, 240 μL of the developing reagent, and 1200 μL of the wash buffer were injected into the first main chamber 123 , the second main chamber 125 , and the third main chamber 127 via the first air vent 122 , the second air vent 124 , and the third air vent 126 respectively.
The combined discs were then rotated at 1200 RPM, the first release speed in this case, to transfer the wash buffer into the detection chamber 24 for reactions. The volume of the wash buffer in each reaction unit 2 was 200 μL since the wash buffer had been evenly distributed into six reaction units 2 on the combined disc. After then, the wash buffer in each reaction unit 2 rinsed the detection chamber 24 and flowed into the waste chamber 25 . Notably, the magnetic beads 3 were kept in the detection chamber 24 by the attraction from the second magnetic units 1311 under the first release speed.
The combined discs were further rotated at 2400 RPM, the second release speed in this case, to transfer the developing reagent into the detection chamber 24 for reactions. The volume of the developing reagent in each reaction unit 2 was 40 μL since the developing reagent had been evenly distributed into six reaction units 2 on the combined disc. After then, the developing reagent in each reaction unit 2 developed colors in the detection chamber 24 and flowed into the waste chamber 25 . Notably, the magnetic beads 3 were kept in the detection chamber 24 by the attraction from the second magnetic units 1311 under the second release speed.
The combined discs were then rotated at 3600 RPM, the third release speed in this case, to transfer the stop solution into the detection chamber 24 for reactions. The volume of the stop solution in each reaction unit 2 was 20 μL since the stop solution had been evenly distributed into six reaction units 2 on the combined disc. After then, the stop solution flowed into the waste chamber 25 . Notably, the magnetic beads 3 were kept in the detection chamber 24 by the attraction from the second magnetic units 1311 . The result of this quantitative hCG testing is shown in FIG. 8 . According to FIG. 8 , the correlation coefficient of the result is about 0.997, which confirms that the embodied centrifuge/magnet-based analyzer used in the first experiment is highly accurate and sensitive.
The second experiment was conducted to determine the concentration of CA-125, also known as cancer antigen 125, in samples. Similar to FIG. 7 , the magnetic beads 3 conjugated with the primary antibody, the secondary antibody, and six samples were injected into the sample chamber 22 . The six samples, each is 15 μL in volume, are products of a serial dilution, which is originated from a known source. The concentration of each sample is listed in Table 2.
TABLE 2
Sample
Sample
Sample
Sample
Sample
Sample
G
H
I
J
K
L
CA-125
0
25
50
100
200
400
(mIU/mL)
In particular, the volume of the magnetic beads 3 is 35 μL and the secondary antibody is 30 μL. Furthermore, 360 μL of the stop solution, 480 μL of the developing reagent, and 960 μL of the wash buffer were all injected into the first main chamber 123 , the second main chamber 125 , and the third main chamber 127 via the first air vent 122 , the second air vent 124 , and the third air vent 126 respectively.
The combined discs were first rotated at 800 RPM, the incubation speed in this case, to transfer the samples, the magnetic beads 3 , and the secondary antibody to the incubation chamber 23 and the detection chamber 24 . The magnetic beads 3 were shuttling in a way similar to that in the first experiment.
The combined discs were then rotated at 1700 RPM to transfer the wash buffer into the detection chamber 24 for reactions. The volume of the wash buffer in each reaction unit 2 was 160 μL since the wash buffer had been evenly distributed into six reaction units 2 . After then, the wash buffer in each reaction unit 2 flowed into the waste chamber 25 . Notably, the magnetic beads 3 were kept in the detection chamber 24 by the attraction from the second magnetic units 1311 under the first release speed.
The combined discs were further rotated at 2800 RPM to transfer the developing reagent into the detection chamber 24 for reactions. The volume of the developing reagent in each reaction unit 2 was 80 μL since the developing reagent had been evenly distributed into six reaction units 2 . After then, the developing reagent in each reaction unit 2 developed colors in the detection chamber 24 and flowed into the waste chamber 25 . Notably, the magnetic beads 3 were kept in the detection chamber 24 by the attraction from the second magnetic units 1311 under the second release speed.
The combined discs were then rotated at 4100 RPM, the last release speed in this case, to transfer the stop solution into the detection chamber 24 for reactions. The volume of the stop solution in each reaction unit 2 was 60 μL since the stop solution had been evenly distributed into six reaction units 2 . After then, the stop solution flowed into the waste chamber 25 . Notably, the magnetic beads 3 were kept in the detection chamber 24 by the attraction from the second magnetic units 1311 .
The result of this quantitative CA-125 testing is shown in FIG. 9 . According to FIG. 9 , the correlation coefficient of the result is about 0.993, which confirms that the embodied centrifuge/magnet-based analyzer used in the second experiment is high accurate and sensitive.
Some embodiments of the present invention have potential in the point-of-care testing (POCT) industry. POCT devices are characterized in fast analysis process and high portability. POCT devices promise a future allowing healthcare providers in poorly equipped clinics to perform diagnostic tests locally. The POCT technology will soon become an important part to improve global health.
There are many inventions described and illustrated above. The present inventions are neither limited to any single aspect nor embodiment thereof, nor to any combinations and/or permutations of such aspects and/or embodiments. Moreover, each of the aspects of the present inventions, and/or embodiments thereof, may be employed alone or in combination with one or more of the other aspects of the present inventions and/or embodiments thereof. For the sake of brevity, many of those permutations and combinations will not be discussed separately herein.
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The present invention provides centrifuge/magnet-based analyzers and methods of operating thereof. The analyzer comprises three discs sandwiched together, in which each disc has difference functions. The top disc comprises magnetic units configured in patterns, whereas the bottom disc comprises tracks and magnetic units free to move in the tracks. The magnetic field co-generated by the top disc and the bottom disc attracts the magnetic beads in the intermediate disc to move and thus facilitates the reactions in the intermediate disc.
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FIELD
[0001] The invention relates to a system for engine oil storage and filtration in an internal combustion engine, comprising at least one oil storage device as part of an engine oil circuit, at least one filtration device, and at least one oil delivery pump.
PRIORITY
[0002] This application claims priority to German Patent Application No. DE 10 2010 011 348.4, filed Mar. 12, 2010, the disclosure of which is hereby incorporated by reference.
BACKGROUND
[0003] What are known above all are pressure oil filters in the oil circuit of internal combustion engines. Said pressure oil filters are connected downstream of the engine oil pump and are attached, usually so as to be exchangeable, to the engine housing or to the cylinder head. The conventional oil filters are afflicted with the disadvantage that they take up a relatively large amount of installation space, in particular because it must be ensured that they are accessible for servicing.
[0004] Pressure oil filters are often attached to an adapter, which necessitates further installation space and entails additional costs. In general, long oil lines lead to the adaptation points, which oil lines must usually be drilled, which can entail high costs and also an additional risk of contamination as a result of drilling residues in the engine block and cylinder head.
[0005] Virtually all pressure oil filters are arranged in the partial flow of the pump, such that contaminated oil is purified only gradually (partial flow principle).
[0006] To keep the filter element free from high oil pressures in particular in cold operating states of the engine or of the internal combustion engine, pressure oil filters generally contain a bypass valve, such that unfiltered oil is initially supplied to the engine lubricating points at low oil temperatures. Such an arrangement is complex and entails additional costs.
[0007] DE 197 35 444 A1 discloses an oil filter insert for oil pans of engines and transmissions with integrated suction oil filtration and pressure oil filtration, wherein a filter unit for suction filtration and a filter unit for pressure filtration of engine or transmission oils is arranged on a seal carrier frame. The oil filter insert described in DE 197 35 444 A1 is duly described as being suitable for engine oil filtration but is designed and can be used only for transmission oil filtration of automatic transmissions, in particular because significantly larger engine oil volume flows are circulated in engine oil circuits of internal combustion engines.
SUMMARY
[0008] The invention is based on the object of providing a system for engine oil storage and filtration in an internal combustion engine, which system is improved in relation to known systems for engine oil filtration with regard to functional reliability and costs and with regard to the required installation space.
[0009] The object is achieved firstly by means of a system for engine oil storage and filtration in an internal combustion engine, comprising at least one oil storage device as part of an engine oil circuit, at least one filtration device, and at least one oil delivery pump, wherein the system is characterized in that the filtration device is connected upstream of the oil delivery pump in relation to the delivery direction of the oil. Such a system can advantageously be integrated into the engine oil pan and thereby utilizes hitherto unutilized installation space in the crankcase or engine housing and the oil pan.
[0010] Within the context of the invention, an oil storage device may be understood to mean both an oil pan in the conventional sense and also an oil container of a dry pan lubrication facility.
[0011] The system according to the invention also has the advantage that the attachment of the filtration device in the oil pan does not necessitate any further oil lines, threaded bores and sealing points in or on the engine housing.
[0012] In one advantageous variant of the system according to the invention, only suction filtration is provided. Contrary to previous opinions, it is entirely possible for the filtration device to be designed with such low flow resistances that pressure oil filtration can be dispensed with.
[0013] In one advantageous variant of the system according to the invention, the filtration device is arranged in the main flow of the oil delivery pump, or the oil delivery pump is connected directly at the suction side to the filtration device.
[0014] The filtration device is expediently arranged within the oil storage device. Since the filtration device itself is fully flooded with oil, the associated volume loss within the oil storage device or oil pan is relatively small.
[0015] In a particularly expedient variant of the system according to the invention, it is provided that the filtration device is designed as an exchangeable filter insert of the oil pan.
[0016] The filtration device, with the exception of the filter medium, may also be formed as an integral constituent part of the oil pan.
[0017] The filtration device may for example be accessible via a correspondingly designed inspection opening in the oil pan. In a particularly advantageous variant of the invention, an oil drainage device, in the form of an oil drainage screw or the like arranged in an inspection cover, is arranged in said inspection opening.
[0018] The filter insert expediently comprises at least one filter housing and at least one filter element provided in the filter housing.
[0019] In a particularly advantageous variant of the system, it is provided that the filter element comprises, in the flow direction of the oil, at least one first and one second filtration layer, wherein the filter medium of the first filtration layer is more dense than the filter medium of the second filtration layer. It is for example possible for the filter medium of the first filtration layer to be formed as a relatively dense filter nonwoven or filter fabric, and the filter medium of the second filtration layer may be formed for example as an open filter screen.
[0020] It is particularly expedient for the first and second filtration layers to be spaced apart from one another in regions and for the first filtration layer to be provided, in the regions spaced apart from the second filtration layer, with flow bypasses. In this way, it is ensured in particular when the engine oil is cold that the flow resistance of the filtration device is kept within predefined limits.
[0021] It has proven to be particularly advantageous for a passage hole arrangement to be provided as flow bypasses in the first filtration layer. When the engine oil is relatively cold, a part of the oil will initially flow through the passage hole arrangement in the first filtration layer, wherein said oil is subjected to fine filtration by means of the second filtration layer. In contrast, the first filtration layer subjects the oil to extra-fine filtration. The desired oil purity is generated overall in that the oil, with increasing temperature, which is associated with a continuously decreasing viscosity, is conducted to an ever greater degree through the filter medium of the first filtration layer. The proportion of the oil flowing through the openings of the first filter medium continuously decreases with increasing temperature.
[0022] The passage hole arrangement of the first filtration layer is designed in terms of form and size as demanded by the respective application or engine type. The design parameters include substantially the pump suction power, the pump delivery power, the specific introduction of dirt into the oil occurring as a result of operation, and the viscosity of the oil used.
[0023] The first filtration layer is preferably folded (pleated). The passage hole arrangement may be provided both in the region of the folds of the fold arrangement and also in the region of flanks of the folds. The passage hole arrangement may be of any size, form and configuration. This applies both to the design of the holes themselves and also to the configuration of the passage hole arrangement in the filtration layer. Said arrangement may be provided in the form of a repeating pattern on the filtration layer. The configuration of the passage hole arrangement may be either symmetrical or asymmetrical.
[0024] The first filtration layer may for example take the form of a cylindrical, pleated filter cartridge which is surrounded by a second filtration layer for example in the form of a cylindrical metal grate.
[0025] Chambers are advantageously provided in each case between the first and second filtration layers, the delimiting walls of which chambers are formed partially by the flanks of the folds of the first filtration layer. The chambers are defined by the flanks of the folds of the first filtration layer and of the lateral surface defined by the second filtration layer.
[0026] In one expedient variant of the system according to the invention, it is provided that the filter housing has at least one intake connecting piece for the suction-side connection of the oil pump.
[0027] In one advantageous embodiment of the system according to the invention, it is provided that the pressure losses generated in the filtration device under normal operating conditions are ≦400 mbar.
[0028] The filter housing is expediently arranged at the lowest point of the oil pan.
[0029] The filter housing preferably comprises at least one partial-flow duct which connects the intake connecting piece directly to the, in the installed position, upper region of the filter housing. The intake connecting piece may for example open out into the lower part or lower region of the filter housing. Air/gas which collects under some. circumstances approximately in the upper region of the filter housing is drawn, preferably utilizing the venturi effect, via the partial-flow duct into the main intake flow of the oil pump in such a way that cavitation in the pump is reliably prevented.
[0030] The invention also relates to a filter insert having the features of one of the preceding claims.
[0031] The object on which the invention is based is finally achieved by means of a method for engine oil circulation and filtration in an internal combustion engine, which method is characterized in that the engine oil is subjected to only suction oil filtration.
[0032] According to the invention, the filtration of the oil takes place in multiple stages, with a first filtration being carried out with a relatively dense filter medium and a second filtration being carried out with a relatively open filter medium.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] The invention will be explained below on the basis of an exemplary embodiment illustrated in the drawings, in which:
[0034] FIG. 1 shows a section through a filtration device according to the invention in the installed situation,
[0035] FIG. 2 shows a sectional view through the filter housing, and
[0036] FIG. 3 shows an exploded view of the filter element inserted into the filter housing.
DETAILED DESCRIPTION
[0037] The filter insert 1 according to the invention comprises a filter housing 2 composed of thermoplastic material and a filter element 3 inserted into the filter housing 2 .
[0038] The filter insert 1 is arranged within an oil pan 4 of an internal combustion engine of a passenger vehicle or utility vehicle in the region of an inspection opening of the oil pan 4 . The inspection opening 5 is situated at the, in the installed position, lowest point of the oil pan 4 , and said inspection opening 5 is closed off by means of an inspection cover 6 . The filter housing 2 defines an approximately cylindrical receiving space for the filter element 3 , which is likewise cylindrical, as illustrated in FIG. 3 . Of corresponding design are the inspection opening 5 and the inspection cover 6 , which is provided with a central oil drainage opening 7 which in turn is closed off by means of an oil drainage screw 8 with the interposition of an O-ring seal 9 .
[0039] The filter element 3 is held in its position with respect to the filter housing 2 by means of webs 10 attached to the inspection cover 6 . The webs 10 are supported against an, in the installed position, lower cover 11 of the filter element 3 . The webs 10 serve simultaneously to define the spacing between the filter element 3 and the inspection cover 6 , in such a way that the inlet 12 of the filter element 3 is left free.
[0040] The filter element 3 is illustrated in an exploded view in FIG. 3 . Said filter element 3 comprises a first, inner filter medium 13 in the form of a pleated fabric or nonwoven filter, and a second filter medium 14 , which surrounds the first filter medium 13 , in the form of a wire cage or wire grate. In the drawing, the mesh spacings of the second filter medium are illustrated as being exaggeratedly large.
[0041] The first filter medium 13 is designed as an extra-fine filter medium, whereas the second filter medium 14 is designed as a fine filter medium. The first filter medium 13 is designed as a relatively dense filter medium, whereas the second filter medium 14 is designed as a relatively open filter medium.
[0042] In the exemplary embodiment described, the engine oil to be filtered flows initially through the first filter medium 13 and then through the second filter medium 14 . The oil flows from the center of the filter element 3 outward into the filter housing 2 , and from there to the oil pump (not illustrated), as will be explained further below.
[0043] Within the context of the invention, however, an oil flow from the outside through the filter media into the center of the filter element 3 and from there to the oil pump is also possible. This requires a corresponding arrangement of the filter media relative to one another.
[0044] As can be seen in particular from a juxtaposition of FIGS. 3 and 1 , the first filter medium 13 is pleated (folded), the flanks 15 of the first filter medium 13 being provided with a passage hole arrangement 16 .
[0045] In the exemplary embodiment described, the passage hole arrangements are selected such that two encircling hole ducts are formed, wherein the size and configuration of the passage hole arrangement and also the number of holes are a matter of design. In each case two opposite flanks 15 of the first filter medium and the associated lateral surface of the second filter medium 14 define a chamber with an approximately triangular cross section. In the region of each chamber, the first filter medium 13 is spaced apart from the second filter medium 14 . As a result of the pleated design of the first filter medium 13 , a multiplicity of folds and chambers are formed over the circumference of the first filter medium 13 .
[0046] As can be seen from FIG. 3 , the second filter medium surrounds the first filter medium 13 . The arrangement is held together by means of an upper cover 17 and the lower cover 11 and forms a filter cartridge/filter element 3 which is detachably inserted into the filter housing 2 which is arranged in a positionally fixed manner in the oil pan 4 , and said filter cartridge/filter element 3 is held in the filter housing 2 by means of the webs 10 . In particular, the first filter medium may for example be cohesively connected to the upper and lower covers 17 , 11 .
[0047] The second filter medium 14 may be formed either from steel/high-grade steel or for example as a polyamide grate.
[0048] The lower cover 11 of the filter element 3 is sealed off by means of an O-ring seal 18 against a sealing seat 19 , which is formed as a collar, of the filter housing 2 . Within the filter housing 2 , the filter element 3 is centered by means of a peg 20 which projects inward into the housing.
[0049] After the inspection cover 6 of the oil pan 4 is detached, the filter element 3 can be detached or removed as a whole from the filter housing 2 in order to be exchanged.
[0050] The filter housing 2 (see FIG. 2 ) comprises a partial-flow duct 21 which extends from the uppermost delimitation of the filter housing 2 into an intake connecting piece 22 which is connected directly to the suction side of an engine oil pump (not illustrated). Furthermore, the intake connecting piece 22 opens out directly into the lower part of the filter housing 2 via the intake opening 23 . In the upper region of the filter housing 2 , the partial-flow duct 21 is connected via the intake opening 24 to that volume of the filter housing 2 which is provided for the filter element 3 . The lower intake opening 23 is dimensioned so as to be larger than the intake opening 24 , such that the main oil flow sucked in through the intake opening 24 generates a suction action in the partial-flow duct 21 , with the effect that any air which collects in the upper region of the filter housing 2 , for example after an oil filling process or in the event of foaming oil, is concomitantly drawn into the intake connecting piece 22 in such a way that cavitation in the engine oil pump is reliably prevented.
[0051] On account of the vacuum generated by the engine oil pump, the engine oil is drawn through the inlet 12 , which is designed as an oval inlet opening in the lower cover 11 of the filter element 3 , into the interior of the first filter medium 13 . From there, the engine oil flows through the first filter medium 13 and subsequently penetrates through the second filter medium 14 which lies over said first filter medium 13 , wherein in the cold state a partial quantity of the engine oil flows through the passage hole arrangement 16 and passes, through the pockets/chambers generated by the folds of the first filter medium 13 , directly through the second filter medium 14 . As the engine oil warms up further, it penetrates through the relatively dense filter fabric/filter nonwoven of the first filter medium 13 outside the passage hole arrangement, as a result of which extra-fine filtration is realized for the first time.
[0052] On account of the multi-stage design of the filter element 3 , in particular as a result of the provision of a passage hole arrangement 16 with a spacing to the second filter medium 14 , it is possible for the flow resistance upstream of the oil pump and the flow resistance of the entire filtration device to be kept relatively low, such that cavitation in the pump is reliably prevented.
[0053] As a result of the position of the filter insert 1 at the lowest point in the engine in conjunction with the oil drainage device situated directly underneath, during an exchange of the filter element 3 , any loosely adherent dirt is reliably entrained by the oil flowing out and is flushed out of the oil pan.
[0054] The accessibility of the system during a filter exchange is ensured, and does not involve great expenditure because during an associated oil change, work must be carried out at this location in any case when the oil is drained. The filter insert 1 itself is accessed in a simple manner through the inspection cover 6 which is screwed to the oil pan 4 from the outside.
[0055] The operational reliability is increased in that the number of leakage points from the engine to the environment is reduced. Furthermore, the oil pump is protected against damage which may arise on account of unfiltered oil. As a result of the low flow resistance generated by the filter element 3 , the oil pump requires a lower drive power than is necessary with conventional pressure oil filtration. In this way, the efficiency of the pump and therefore of the engine is increased in particular when the engine is cold.
LIST OF REFERENCE NUMERALS
[0000]
1 Filter insert
2 Filter housing
3 Filter element
4 Oil pan
5 Inspection opening
6 Inspection cover
7 Oil drainage opening
8 Oil drainage screw
9 O-ring seal
10 Webs
11 Lower cover, filter element
12 Inlet
13 First filter medium
14 Second filter medium
15 Flanks
16 Passage hole arrangement
17 Upper cover
18 O-ring seal
19 Sealing seat
20 Peg
21 Partial-flow duct
22 Intake connecting piece
23 Intake opening
24 Intake opening
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The invention relates to a system for engine oil storage and filtration in an internal combustion engine, comprising at least one oil storage device as part of an engine oil circuit, at least one filtration device, and at least one oil delivery pump, wherein the system is characterized in that the filtration device is connected upstream of the oil delivery pump in relation to the delivery direction of the oil, with only suction filtration being provided.
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BACKGROUND OF THE INVENTION
This invention relates generally to a method of preparing long-life fresh pasta products on a commercial scale, such as but not solely fresh pasta products from durum wheat flour and eggs, with or without a filling. Where a filling is provided, this would be of the general kind including meat, cheese, bread, vegetables, herbs, spices, etc. More specifically, the invention concerns an improved method of making sheet dough for use in the production of fresh pasta products, with or without a filling.
Throughout the ensuing description and the appended claims, the term "fresh pasta" applies to any pasta products, whether stuffed or otherwise, made on a commercial scale to have a water content in the 25% to 30% range by weight, thereby it will be soft and resilient to the touch like fresh homemade pasta.
It is a well-recognized fact that shortly (2-3 days) after preparation, fresh pasta products will undergo substantial alteration of a bacterial and chemical type, resulting in an unacceptable drastic deterioration of its original organoleptic features, and above all, the appearance of toxic agents. Contamination of fresh pasta is due both to the ingredients employed and the manipulation to which it is subjected during the production process.
Also well known is the fast deterioration of its original organoleptic properties, that is taste, flavor and appearance.
Currently available on the market are products the long-life features (wholesomeness and retention of the original organoleptic properties) features whereof are achieved by cold processing, in particular by freezing freshly prepared foodstuff to -20° C./-25° C. or cooling within the range of 2° to 4° C.
However, this prior procedure has some well recognized complications due to the need for maintaining a cold chain which encompasses production, packaging, storage, transportation, display for sale, under ambient conditions of temperature and humidity which are neither easy to maintain not to control. Thus, the problems are not only of an economical nature, but also technical and sanitary.
SUMMARY OF THE INVENTION
This same Applicant has proposed and tested an alternative procedure based essentially on salting the start dough and suitably heat processing the product as soon as prepared from said dough. This procedure is fully described in Italian Patent No. IT 1199849 by this Applicant and issued on Jan. 5, 1989 and incorporated hereto for reference.
While on the one side this prior procedure can yield fresh pasta products having characteristics which are better than satisfactory from the standpoint of their wholesomeness and preservability over time at ambient temperature (shelf-life), on the other side, it has been found that it could be improved upon to afford increased production output.
In fact, it has been found that, using the above procedure, during the preparation of sheet dough from a salted stock, and through subsequent steps of mechanical manipulation of the same, such as in the course of operations to form and fold over sheet dough sections around a filling to make tortellini, ravioli, etc., tears, voids, and the like material discontinuities may occur which, even if modest in size, still make it necessary that the affected product be discarded.
Since sheet dough processed from dough which has been prepared from the same ingredients, but not salted, exhibits no such drawback as the one noted above, while being subjected to the same mechanical stresses, and since it is well known that the toughness and cohesion viscoelastic characteristics of a dough stock of the kind under consideration and of the sheet dough yielded thereby are tied substantially to the gluten links they include, it has been thought that said problem (formation of tears and the like) is indeed attributable to the presence of salt in the dough stock.
It is judged that the salt added to the dough (at a moisture content of 30 to 32%) fully hydrolyzes, and that the ions released react with some of the functional groups of the gluten chains to combine therewith and neutralize their activeness. As a result, the gluten chains, depleted of a number of active sites, would originate a link or structure with a reduced degree of cross-linking, and hence, reduced strength.
The problem that underlies this invention is to provide a method of preparing fresh pasta products, with or without a filling, having long life features at ambient temperature, which can successfully overcome the above-noted drawbacks while retaining the recognized advantages of the cited prior art.
This problem is solved according to the invention by a method comprising the sequential steps of:
providing a dough stock from ingredients which include durum wheat flour, water, eggs, and salt, said dough stock incorporating salt in an amount between 2.5% and 4% by weight and having a water content in the 30% to 32% range;
forming from said dough stock a web of sheet dough whose fibers are mainly oriented in the longitudinal direction thereof;
lapping said sheet dough into plural overlaid layers; and
rolling and calibrating said overlaid layers in a cross direction to the main orientation of the fibers in said sheet dough.
The salted sheet dough thus obtained showed no tears either during its mechanical processing or on the occasion of subsequent forming into such end products as tortellini and the like. It is therefore considered that by cross rolling the plurality of overlaid layers of "salted" sheet dough, a higher number of "encounters and crossings" is achieved statistically between gluten chains, thereby at least the same degree of cross-linking is re-established as the sheet dough would have if formed from a salt-free dough stock.
This benefit is confirmed, moreover, by the improved cooking characteristics of products made of the salted sheet dough according to this invention.
The invention features and advantages will be more clearly apparent from the following detailed description, given by way of illustration only with reference to the accompanying drawings, where:
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 and 2 are a side view and a front view, respectively, of an apparatus for implementing the method of this invention.
DETAILED DESCRIPTION OF THE INVENTION
A dough stock was prepared from durum wheat flour, eggs (four eggs per kilogram flour), salt to an amount within the 3% to 5% range by weight of the durum wheat flour, and a sufficient amount of water. The resulting dough had solid-to-plastic consistency and a moisture content of 32%.
This dough stock was worked into a sheet which showed to be resilient solid-like with a moisture content of 30% and fibers mainly oriented along the longitudinal direction of the sheet.
This sheet dough, indicated at 19 in FIGS. 1 and 2, was then taken to by a conveyor 1 to a lapper device 6. Through this lapper device, the sheet dough 19 was laid into plural overlaid layers on a conveyor belt 13, and the plurality of overlaid layers, essentially forming a "pack" 20, was delivered on the same conveyor 13 to a rolling/calibrating unit 17.
The plurality of overlaid layers of such a pack was roll processed for several times, and finally calibrated to yield a new sheet dough 21 having a predetermined thickness. It should be noted that, in accordance with this invention, the rolling and calibrating steps were carried out in a cross direction to the direction of lay of the fibers in the sheet dough 19 such as produced.
The sheet 19 lapping on the conveyor 13 was performed by successively folding the same over, with the folds oriented transversely to the orientation of the sheet dough fibers and for a predetermined number of times to suit particular organoleptic and cooking characteristics required of the type of pasta product into which the sheet dough was being worked by the method of this invention.
The sheet 21 was then used to form pasta products to be stored fresh, such as tortellini, using a conventional filling. During the sheet forming of operations, or rather forming portions thereof, and its gathering around a predetermined amount of a suitable filling, no tears or cracks or the like faults were to be observed in the sheet dough.
The tortellini (like other products) formed from the sheet 21 had a moisture content of 30%, and they all had the features of resilient solid bodies, soft to the touch. The resulting pasta products were later subjected to heat pasteurization processing at a temperature in the 90° to 102°-103° C. range for a time period varying between 105 and 120 seconds. At the end of the process, the moisture content of the tortellini (like that of the other pasta products was still of approximately 30%.
Subsequently, these products were subjected to partial drying in an environment at a temperature of about 80°-85° C., and at a relative humidity of 23%. The latter treatment was applied for 5-7 minutes, and thereafter, the moisture content of the pasta products showed to have dropped down to 25% with a water activity Aw of 0.85-0.87.
The products were then fed into a packaging station where they were packaged into appropriate containers in an inert gas environment, which containers were then sealed, they being formed from a suitable, substantially oxygen-impervious material. Following heat stabilization in a microwave oven to about 90° C. for 8-10 minutes, the packaged product was handed to storage, whence samples were picked up and tested for their moisture content, water activity, and bacterial charge. The test results were better than satisfactory.
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A sheet of a fresh dough formed from a dough stock incorporating up to 4% salt is subjected to cross rolling. The fresh pasta product obtained from such sheet dough has extended shelf-life while retaining the original organoleptic properties unaltered.
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CLAIM OF PRIORITY
[0001] This Patent Application claims priority from US Provisional Patent Application No 61/692,676 entitled MULTI-PURPOSE BAG which was filed on Aug. 23, 2012, and names common inventor Grossman.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to retail shopping bags, more particularly, the invention relates to multi-purpose retail shopping bags.
PROBLEM STATEMENT
Interpretation Considerations
[0003] This section describes the technical field in more detail, and discusses problems encountered in the technical field. This section does not describe prior art as defined for purposes of anticipation or obviousness under 35 U.S.C. section 102 or 35 U.S.C. section 103. Thus, nothing stated in the Problem Statement is to be construed as prior art.
Discussion
[0004] Retailers and those in the recycling-movement have long-struggled to find productive alternative/secondary uses for used shopping bags. For example, some bags have alternative uses such as lining small trashcans (indeed, containers are made to be used with plastic shopping bags). But, these alternative uses are certainly not optimal, often just accumulate in a drawer/bag or other container, and because they can be both eyesores when blowing around lawns as well as dangerous to birds and other animals, plastic grocery bags are targeted for banning by environmental groups. The result is that in many municipalities, various types of shopping bags are banned by law. Other bags have been designed for specific secondary purposes, such bags that unfold for use as a napkin or a table cloth. However, these single use-case bags are unpractical; after all, very few consumers go on a picnic or set a table for every shopping bag they take home.
[0005] Recently, cloth reusable bags have gained popularity. However, studies show that these reusable bags harbor dangerous bacteria after just a few uses. The result has been that there are no compelling alternatives that are safe, environmentally conscious, and affordable. The present invention provides an apparatus that overcomes these disadvantages and provides a new variety of ways to reuse a shopping bag.
BRIEF DESCRIPTION OF THE DRAWINGS AND TABLE
[0006] Various aspects of the invention, as well as an embodiment, are better understood by reference to the following detailed description. To better understand the invention, the detailed description should be read in conjunction with the drawings, in which:
[0007] FIG. 1 shows an unfolded view of the inventive bag;
[0008] FIG. 2 illustrates the bag as manufactured; and
[0009] FIG. 3 is a top-down view of the bag.
DETAILED DESCRIPTION OF THE INVENTION
Interpretation Considerations
[0010] When reading this section (which describes an exemplary embodiment of the best mode of the invention, hereinafter “exemplary embodiment”), one should keep in mind several points. First, the following exemplary embodiment is what the inventor believes to be the best mode for practicing the invention at the time this patent was filed. Thus, since one of ordinary skill in the art may recognize from the following exemplary embodiment that substantially equivalent structures or substantially equivalent acts may be used to achieve the same results in exactly the same way, or to achieve the same results in a not dissimilar way, the following exemplary embodiment should not be interpreted as limiting the invention to one embodiment.
[0011] Likewise, individual aspects (sometimes called species) of the invention are provided as examples, and, accordingly, one of ordinary skill in the art may recognize from a following exemplary structure (or a following exemplary act) that a substantially equivalent structure or substantially equivalent act may be used to either achieve the same results in substantially the same way, or to achieve the same results in a not dissimilar way.
[0012] Accordingly, the discussion of a species (or a specific item) invokes the genus (the class of items) to which that species belongs as well as related species in that genus. Likewise, the recitation of a genus invokes the species known in the art. Furthermore, it is recognized that as technology develops, a number of additional alternatives to achieve an aspect of the invention may arise. Such advances are hereby incorporated within their respective genus, and should be recognized as being functionally equivalent or structurally equivalent to the aspect shown or described.
[0013] Second, the only essential aspects of the invention are identified by the claims. Thus, aspects of the invention, including elements, acts, functions, and relationships (shown or described) should not be interpreted as being essential unless they are explicitly described and identified as being essential. Third, a function or an act should be interpreted as incorporating all modes of doing that function or act, unless otherwise explicitly stated (for example, one recognizes that “attaching” may be done by hook-and-loop attachment (such as Velcro®), snaps, hooks, belts, etc., and so a use of the word attaching invokes all methods of attachment known in and anticipated by the art, and all other modes of that word and similar words).
[0014] Fourth, unless explicitly stated otherwise, conjunctive words (such as “or”, “and”, “including”, or “comprising” for example) should be interpreted in the inclusive, not the exclusive, sense. Fifth, the words “means” and “step” are provided to facilitate the reader's understanding of the invention and do not mean “means” or “step” as defined in §112, paragraph 6 of 35 U.S.C., unless used as “means for—functioning—” or “step for—functioning—” in the Claims section. Sixth, the invention is also described in view of the Festo decisions, and, in that regard, the claims and the invention incorporate equivalents known, unknown, foreseeable, and unforeseeable. Seventh, the language and each word used in the invention should be given the ordinary interpretation of the language and the word, unless indicated otherwise.
[0015] It should be noted in the following discussion that acts with like names are performed in like manners, unless otherwise stated. Of course, the foregoing discussions and definitions are provided for clarification purposes and are not limiting. Words and phrases are to be given their ordinary plain meaning unless indicated otherwise. The numerous innovative teachings of present application are described with particular reference to presently preferred embodiments.
Functional Description of the Invention
[0016] In one embodiment, the invention is a retail carrier or grocery tote bag made with a rag material. It is not only a reusable item, but a multi-use reusable bag. For example, it could be reused as a bag until it reaches its usable life. It could then can be rinsed and or sanitized and used for a rag. In one embodiment, the material the body of the bag is made of is chosen to be useful for many household chores including wiping down counters, washing windows or even washing/drying off a car.
[0017] Once brought home from the store the bag can be stored in a drawer or cabinet and used whenever normally a rag would be needed to clean up a spill, etc. Because the bags are reused in many ways, multiple times, less trash enters the environment, and the need for plastic bags, which often become trash in trees and can even kill birds and fish. Additionally, a bag may have a logo printed thereon, and the logo may be printed with ink that expresses itself when the bag material becomes wet, or reaches a certain temperature (hot or cold).
Description of the Drawings
[0018] The invention, a reusable, multi-purpose bag apparatus, is described in simultaneous reference to FIGS. 1-3 , in which FIG. 1 shows an unfolded view of the inventive bag 200, FIG. 2 illustrates the bag 200, and FIG. 3 is a top-down view of the bag 200.
[0019] The bag 200 is preferably comprised of a generally rectangular body 100 having a polyester and wood pulp combination non-woven fabric. However, many non-woven fabrics are usable to achieve the objectives of the invention. For example a list of exemplary non-woven fabrics is listed in Table 1.
[0000]
TABLE 1
Alternative Non-Woven Fabrics
Spun-Lace Material
Polypropylene
Polyethylene
Polylactic Acid
Polyester
Cotton
Wood Pulp
Paper
[0020] Alternatively, the rag material is made with a paper-like wood fiber pulp and a small amount of polyester (or other polymer) fiber material laminated together via water lace bonding. In an alternative embodiment, the pulp material is a synthetic pulp. In one embodiment, the ragbag material can be 30 g heavier depending on the strength requirement of the final bag to be produced. For the medium weight 60 Gsm material, it is preferred to use approximately 35 G wood fiber pup +25 G of Polyester. Water pressure helps to create strength in the this process by bonding shorter wood fibers to the longer fibers of the polymer material. Preferably, the material absorbency potential is approximately about five times the weight of the material, so 60 grams ragbag material generally can absorb at least 300 grams of water. The percentage of wood fiber influences absorbability, meaning that liquids usually absorb better into “cloth” with more wood material in it. The desired strength will ultimately determine the ratio of paper (or other pulp) to polymer.
[0021] The body 100 is formed to define the bag 200 . The bag 200 has a top 230 that opens to define a mouth 210 , and a closed bottom 220 formed by a fold in the body 100 . When folded, the bag 200 has a generally rectangular first panel 110 and a generally rectangular second panel 120 , each panel 110 , 120 having a top area 112 , 122 located proximate to the top 230 of the bag 200 and each panel 110 , 120 having a first side edge 132 and second side edge 134 . The top area 112 of the first panel 110 and the top area 122 of the second panel 120 have holes 114 , 124 therein that are usable as handles. Alternative handle embodiments include die-cut handles, or heavy strips of material that are looped and then utilize a Polymer with EVA to “weld” the ends of the strips to the inside of the bag, for example. Of course, upon reading this disclosure, alternative methods of creating bag handles will be readily apparent to those of ordinary skill in the art without departing from the invention.
[0022] The first panel 110 is coupled to the second panel 120 at the first panel edge 132 and the second panel edge 134 via seals comprising Ethyl Vinyl Acetate (EVA). Shown in FIG. 1 are strips 142 , 144 that may alternatively be actual strips of a polymer containing a high concentration of EVA. The preferred process uses strips of Polymer with a high EVA concentration and, by using heat, melts the Polymer strips 142 , 144 between the first panel 110 and the second panel 120 .
[0023] Alternative methods of attaching/sealing the panel edges 132 , 134 include using a sufficient quantity of EVA to saturate each section (defined by are area covered by the strips 142 , 144 ) of each panel 110 , 120 to be attached, and using hot melt glue, for example. Of course, other methods and systems for attaching the panels 110 , 120 are readily apparent to those of ordinary skill in the art upon reading the present disclosure, and are incorporated in the scope of the invention.
[0024] Additionally, bags may be created having a third seam such that a large roll of material formed into a “tube” and then cut in the middle to create two bags at a time. This third seam exists near the bottom of each bag where the tube is formed.
[0025] In one embodiment special inks are used to print on the bag 200 . For example, some inks are sensitive to temperature (either hot or cold), while others are sensitive to moisture. Accordingly, special advertising/messaging effects can be generated via the bags. For example, a promotional message could be expressed when a chilled beverage is placed in the bag 200 (i.e. “your beverage is ice cold”), which changes to a second message when the beverage is removed from the bag and it warms to a pre-known temperature (i.e. “go out and buy brand X”). Additionally, the bag may express a third message when the bag is disassembled to be used as a rag and wetted (i.e. “wouldn't you rather be drinking X now?”).
[0026] Though the invention has been described with respect to specific preferred embodiments, many variations and modifications will become apparent to those skilled in the art upon reading the present application. Specifically, the invention may be altered in ways readily apparent to those of ordinary skill in the art upon reading the present disclosure. It is therefore the intention that the appended claims and their equivalents be interpreted as broadly as possible in view of the prior art to include all such variations and modifications.
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The invention disclosed herein provides a shopping bag that has multiple alternative uses. It is emphasized that this abstract is provided to comply with the rules requiring an abstract that will allow a searcher or other reader to quickly ascertain the subject matter of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. 37 CFR 1.72(b).
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[0001] This patent application is a continuation-in-part of U.S. patent application number Ser. No. 13/897,304, filed on May 17, 2013, which claims priority to provisional application number 61/648636, which was filed on May 18, 2012.
FIELD
[0002] Certain embodiments of the invention are generally related to articles of clothing adaptable for self-donning and/or donning and doffing by another onto a wearer.
BACKGROUND
[0003] Variety of garments exists on the market for self-donning or donning by another onto wearer. Some of these garments may be used by individuals with medical needs or those with certain physical challenges. Some of these garments allow easy access to certain parts of the body but require efforts by medical staff or the wearer. Other garments feature open designs allowing staff to quickly access bodily areas at the expense of privacy of patients.
[0004] Therefore there is a need for garments that allow easy access to body parts for treatment and medical or other purposes while maintaining privacy and needless exposure. Certain embodiments of the invention provide such advantage as well as other advantages.
[0005] Certain embodiments of the invention may include garments adaptable for self-donning and for donning by another onto a wearer. For example, a garment according to certain embodiments, may include two longitudinal panels. Each longitudinal panel may be operatively attached to each other. Each panel may have a waistband portion, a hip portion and a leg portion. Each longitudinal panel may include at least one cooperating and fastening material that may be disposed substantially along the longitudinal hip and leg portions. Each panel may be moveable between a substantially flat open position and a second closed wearable position where each first and second cooperating and fastening materials of each panel may join to form outer seam of each panel. The cooperating and fastening material may include strips, spots, of cooperating materials that may include mating components.
[0006] Other systems, methods, aspects, features, embodiments and advantages of the invention disclosed herein will be, or will become, apparent to one having ordinary skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, aspects, features, embodiments and advantages be included within this description, and be within the scope of the accompanying claims. This summary is provided merely to introduce certain concepts and not to identify any key or essential features of the claimed subject matter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] It is to be understood that the drawings are solely for purpose of illustration.
[0008] Furthermore, the components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the system disclosed herein. In the figures, like reference numerals designate corresponding parts throughout the different views.
[0009] FIG. 1 shows an embodiment according to certain aspects of the invention in an open position;
[0010] FIG. 2 shows another embodiment according to certain aspects of the invention in closed position;
[0011] FIG. 3 shows a wearer doffing a certain embodiment of the invention;
[0012] FIG. 4 shows an expanded view of certain features of FIG. 3 ;
[0013] FIG. 5 shows another embodiment according to some aspects of the invention;
[0014] FIG. 6 shows some aspects of the embodiment shown in FIG. 5 .
[0015] FIG. 7 shows an alternative embodiment of some aspects of the invention disclosed in FIG. 5 .
[0016] FIG. 8 shows some aspects of the embodiment shown in FIG. 5 .
[0017] FIG. 9 shows a side view of certain embodiment disclosed in FIG. 6 .
[0018] FIG. 10 shows a side view of certain embodiment disclosed in FIG. 6 in an open position.
[0019] FIG. 11 shows a side view of certain embodiment disclosed in FIG. 6 in a closed position.
DETAILED DESCRIPTION
[0020] The following detailed description, which references to and incorporates the drawings, describes and illustrates one or more specific embodiments. These embodiments, offered not to limit but only to exemplify and teach, are shown and described in sufficient detail to enable those skilled in the art to practice what is claimed. Thus, for the sake of brevity, the description may omit certain information known to those of skill in the art.
[0021] FIG. 1 shows certain embodiment according to certain aspects of the present invention. A Garment 100 may include at least two panels, a right panel 110 and a left panel 120 . Right panel 110 may include a waist portion 112 , a hip portion 114 , and a leg portion 116 . Left panel 120 may include a waist portion 122 , a hip portion 124 , and a leg portion 126 . Left panel 120 may include cooperating and fastening material 128 that may have the form of a substantially longitudinal strip 130 or semi-continuous or plurality of dots or any other forms. Strip 130 may be disposed at edge 132 in leg portion 126 of panel 120 . Strip 130 may be spatially distanced from strip 134 , which may include cooperating and fastening material 133 . Right panel 110 may include cooperating and fastening material 135 that may be in the form of substantially continuous strip 136 , or semi-continuous or plurality of dots, which may be disposed adjacent edge 140 . Right panel 110 may also include fastening and cooperating materials 141 in the form of continuous or substantially continuous strip 142 , which may also be in the form of plurality of dots or any other forms.
[0022] FIG. 1 describes a garment 100 configured for physically challenged individuals. FIG. 1 shows garment 100 in an open position to allow individuals with physical challenges to sit on top of garment 100 aligning his left and right legs with right panel 110 and left panel 120 . To turn open garment 100 to a wearable garment, the individual may match strips 130 with strip 134 , and strip 136 with strip 142 . It should be noted that said strips may be joined in other ways. By linking the fastening and cooperating materials, the wearer transforms the open garment into a closed wearable garment with minimum physical effort. Cooperating and fastening materials may join to form outer seams 210 and 212 as shown in FIG. 2 .
[0023] Certain embodiments of the present invention may be easily donned even by wearers with physical disabilities. Once seated on garment 100 in its flat open state, all the releasable closures, for example, 114 , 116 , 124 and 126 , are brought to the front of the wearer's body and generally proximal to the wearer's midline 150 , where they are most easily accessible to either the wearer or an assistant. The frontal locations of the releasable closures enable the wearer to access all the closures with minimal twisting and bending of the wearer's body. Even in the confines of a wheelchair or hospital bed, the closures are accessible and easily connected. The wearer may be clothed by an aide or assistant without the embarrassment or effort of lifting up to position any parts of the pants underneath or around the wearer's groin area. Certain embodiments of the present invention may minimize what may be a humiliating experience undergone on a daily basis by a wearer who is physically challenged or hospitalized.
[0024] Many variations of cooperating and fastening material types and shapes may be used here. For example, cooperating and fastening materials in the shapes of points, bullets, circles, and so forth, may be used. Variety of materials may be used, such as Velcro, zippers, buttons, snaps, laces, hook and eye, buckles, magnets may be hidden in the garment, electrical joints, electromagnetic contacts, thermo contact, thermoelectric contacts, snap buckles, bolt snaps, and so forth may be employed.
[0025] The present invention is adaptable to various fabrics, patterns, and textures, including fine fabrics such as silk and synthetics, or casual fabrics such as denim or corduroy, to name but a few. The releasable closures may be positioned in locations where conventional pants have fabric seams and, in the case of the fly closure, conventional zippers and buttons, so that the article of clothing of the present invention need not be readily identifiable as specialized clothing.
[0026] FIG. 2 shows certain embodiments of the present invention in a second wearable closed position. A wearer may join parts of hip portion 114 to mating portion 124 , leg portion 116 to portion 126 forming outer seam 210 and 212 and creating waist portion 216 and crotch region 214 , and thereby forming a garment 200 around wearer's body without the need to move or twist wearer's body to don article of clothing. Waist portion 216 may include substantially continuous elastic strip 218 that may extend inside outer top edge 220 .
[0027] FIG. 3 shows some uses of certain embodiments of the article of clothing of the present invention 300 . A wearer 310 may be an individual with certain physical challenges. After donning article of clothing 300 , wearer 310 may need to undergo certain medical or physical tests. Wearer 310 may easily expose any bodily parts by releasing outer seams 210 and/or 212 , which may form a continuous outer seam in certain embodiments. Wearer 310 may expose certain bodily parts without having to move or twist his body and without the need for assistance from others. In FIG. 3 , outer seam is shown as Velcro cooperating and fastening materials 320 . However, variety of designs and materials may be used. For example, cooperating and fastening materials in the shapes of points, bullets, circles, and so forth, may be used. Variety of materials may be used, such as Velcro, zippers, buttons, snaps, laces, hook and eye, buckles, magnets may be hidden in the garment, electrical joints, electromagnetic contacts, thermo contact, thermoelectric contacts, snap buckles, bolt snaps, and so forth may be employed.
[0028] FIG. 4 shows certain embodiment 400 having alternative cooperating and fastening materials 410 including plurality of releasably engaging teeth 412 and 414 to allow wearer 310 to releasably engage and disengage teeth 412 and 414 as desired to expose needed bodily parts for treatment and/or medical attention.
[0029] FIG. 5 shows another embodiment 500 according to certain aspects of the present invention in a closed position. Pants 500 may include a fly portion 502 , shown in a closed position 504 . Fly portion 502 may include a plurality of cooperating elements 507 shown in detail in the following figure, FIG. 6 .
[0030] FIG. 6 shows fly portion 502 in an open position. Cooperating elements 507 may include a plug 512 or plurality of plugs on one side 508 of fly portion 502 , and corresponding plurality of jacks 514 on the other side 510 of fly portion 502 . A wearer can easily open or close fly portion 502 by bringing together plugs 512 and jacks 514 that may operate in snap mechanism or pulling them apart. A wearer with physical challenges can easily open or close the entire fly portion 502 in a quick manner in a hospital or medical environment settings. Additional cooperating elements 516 on side 512 and corresponding elements 518 on side 514 may also be added to allow the wearer to undo or do any portion of pants 501 . Pants 501 may consists entirely of cooperating elements 507 spread out across pants 501 to allow wearer to release any portion of pants 501 . Cooperating elements are not limited to snap mechanisms and may include Velcro, zippers, buttons, laces, hook and eye, buckles, magnets, electrical joints, electromagnetic contacts, thermo contact, thermoelectric contacts, and so forth.
[0031] FIG. 7 shows embodiment 600 according to certain aspects of the present invention. Pants 501 may include fly portion 502 configured to allow physically challenged persons to easily open or close desired portions of pants 501 to respond to medical or physiological needs. Embodiment 600 may include at least two portions, a right portion 602 and a left portion 604 . Portions 602 and 604 may be rectangular, elliptical, or any other shape. Preferably portions 602 and 602 have complimentary shapes. Portion 602 may include releasably coupling mechanism 606 and portion 604 may include releasably coupling mechanism 608 . Releasable coupling mechanisms may include Velcro or similar equivalent couplings. Pants 501 may include a plurality of coupling mechanisms. Pants 501 may be formed entirely from coupling mechanisms 610 and/or 612 allowing physically challenged persons to releasably attached or detach any portions of pants 501 .
[0032] FIG. 8 shows closed position 700 of pants 501 . Portion 606 is shown coupled to portion 608 . A coupling mechanism here may include snap button 614 and corresponding button 616 on the other side. A plurality of snap buttons may be used across pants 501 .
[0033] FIG. 9 shows a side view of an embodiment disclosed in FIG. 6 . Portion 510 may include a plurality of snap bolts 512 spaced apart along portion 510 and a plurality of corresponding snap bolts 514 spaced apart on portion 508 along vertical strips 511 .
[0034] FIG. 10 shows another embodiment including a plurality of snap bolts 514 and 512 disposed on vertical strips 511 in an open position.
[0035] FIG. 11 shows snap bolts 514 and 512 in a closed position releasably securing portions 508 and 510 of fly portion 502 .
[0036] The word “exemplary” is used herein to mean “serving as an example, instance, or illustration.” Any embodiment or variant described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments or variants. All of the embodiments and variants described in this description are exemplary embodiments and variants provided to enable persons skilled in the art to make and use the invention, and not necessarily to limit the scope of legal protection afforded the appended claims.
[0037] The above description of the disclosed embodiments is provided to enable any person skilled in the art to make or use that which is defined by the appended claims. The following claims are not intended to be limited to the disclosed embodiments. Other embodiments and modifications will readily occur to those of ordinary skill in the art in view of these teachings. Therefore, the following claims are intended to cover all such embodiments and modifications when viewed in conjunction with the above specification and accompanying drawings.
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Certain embodiments of the invention may include a garment adaptable for self-donning and for donning by another onto a wearer. The garment may include two longitudinal panels. Each longitudinal panel may be operatively attached to each other. Each panel may have a waistband portion, a hip portion and a leg portion. Each longitudinal panel may terminate with a first and second cooperating and fastening material that may be disposed substantially along the longitudinal hip and leg portions. Each panel may be moveable between a substantially flat open position and a second closed wearable position where each first and second cooperating and fastening materials of each panel may join the second closed wearable position. The cooperating and fastening material may include continuous strips of cooperating materials that may include mating components.
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CROSS-REFERENCE TO RELATED APPLICATIONS
Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
The present invention relates to methods for treating an arsenic-contaminated waste matrix to stabilize the arsenic and reduce arsenic leaching to contaminant acceptable levels. Arsenic, which is carcinogenic in its inorganic form, is identified in the Resource Conservation Recovery Act (RCRA) as a hazardous metal and is reportedly the third most common regulated inorganic contaminant found at Superfund sites.
Specific sources of hazardous waste containing arsenic include:
pesticides and herbicides [MSMA (monosodium methane arsonate), cacodylic acid (dimethyl arsinic acid), sodium arsenite, lead arsenate)],
ammonia still lime sludge from coking operations,
veterinary pharmaceuticals [(RCRA waste listing K084) wastewater treatment sludge, (K101) distillation tar residue from distillation of aniline-based compounds, (K102) residue from use of activated carbon for decolorization],
arsenic sulfide (D004) generated from phosphoric acid purification, and
wood preservative manufacturing wastes.
Other anthropogenic sources of arsenic include:
coal-burning fly ash from energy production
copper, lead and zinc smelter operations
gold mining operations, and
glass manufacturing and cotton gin processing.
While arsenic, like other metals, exhibits a positive valence state, in aqueous materials it usually exists not as a solitary cationic species but as an oxy-anion, typically in a mixture of a trivalent (+3), reduced form (arsenite, AsO 3 3− ) and/or a pentavalent (+5) oxidized form (arsenate, AsO 4 3− ). As a result, technologies that effectively treat other cationic metals are typically not effective for stabilizing arsenic.
The ability of arsenic to change oxidation state under certain environmental conditions poses a challenge to treatment methods because the different oxidation states have different mobilities in the environment. Arsenite is usually more mobile than arsenate. Also, arsenic is amenable to numerous chemical and biological transformations in the environment, which can result in increased mobility. The mobility of arsenic can be controlled by redox conditions, pH, biological activity and adsorption/desorption reactions.
Arsenic stabilization chemistry is complex and is influenced significantly by the chemical speciation of arsenic (valence state, inorganic vs. organic, etc.), the oxidation-reduction potential and acidity/alkalinity of the waste matrix, and the presence of other metals, counter ions, and complexing ligands. Arsenic is often present in waste with lead or chromium. Typical techniques for stabilizing these metals (e.g., treating with phosphate to stabilize lead, or treating with reducing agents to stabilize chromium) can undesirably increase arsenic leachability from wastes. When arsenic and chromium are found in together in the same waste matrix, the contaminants are typically present as chromated copper arsenate (CCA).
According to the U.S. Environmental Protection Agency, slag vitrification at 1,100 to 1,400° C. is the Best Demonstrated Available Treatment (BDAT) for arsenic. In a vitrification process, all forms of arsenic are converted to arsenic oxide, which reacts with other glass-forming constituents and becomes immobilized in the glass formed. In most arsenic stabilization situations, vitrification is impractical, however, because of the high energy costs and a secondary problem of volatilizing arsenic to cause air pollution.
Other known detoxification technologies include chemistries that involve solidification or chemical stabilization. “Solidification” is defined by US EPA as a technique that encapsulates the waste in a monolithic solid of high structural integrity. The encapsulation may be effected by fine waste particles (microencapsulation) or by a large block or container of wastes (macroencapsulation). Solidification does not necessarily involve a chemical interaction between the wastes and the solidifying reagents, but may mechanically bind the waste into the monolith. Contaminant migration is restricted by decreasing the surface area exposed to leaching and/or by isolating the wastes within an impervious capsule. “Stabilization” refers to those techniques that reduce the hazard potential of a waste by converting the contaminants into their least soluble, mobile, or toxic form. The physical nature and handling characteristics of the waste are not necessarily changed by stabilization. These definitions appear on page 2 of Conner, J. R., Chemical Fixation and Solidification of Hazardous Wastes, Van Nostrand Reinhold, New York (1990), which is incorporated herein by reference in its entirety.
U.S. Pat. No. 5,037,479 (Stanforth) discloses a method for treating solid hazardous waste containing unacceptable levels of leachable metals such as lead, cadmium and zinc, which includes the steps of mixing the solid waste with at least two additives, a pH buffering agent and an additional agent which is a salt or acid containing an anion that forms insoluble or non-leachable forms of the leachable metal, each agent being selected from a specified group of agents.
U.S. Pat. No. 5,202,033 (Stanforth et al.) discloses a method for treating solid hazardous waste containing unacceptable levels of leachable metals such as lead, cadmium, arsenic, zinc, copper and chromium, which includes the steps of mixing the solid waste in situ with a phosphate source or a carbonate source or ferrous sulfate. An additional pH controlling agent is optionally added under conditions which support reaction between the additive and pH controlling agent and the metals, to convert the metals to a relatively stable non-leachable form.
U.S. Pat. No. 5,430,235 (Hooykaas et al.) discloses a process for solidifying an arsenic-contaminated matrix as a rock-hard product using high dosages of a clay material, an iron salt, a manganese salt, an oxidizer, and a hydraulic binder such as Portland cement. The process disclosed in U.S. Pat. No. 5,430,235 has several disadvantages. Because of the requirement for a hydraulic binder, the process includes a curing period of 7 days or longer. The process also results in significant bulking (volume increase) of the treated waste materials. If dosage levels are lower than those identified as preferred, it is difficult to achieve solidification.
U.S. Pat. No. 5,347,077 (Hooykaas et al.) discloses a process for solidifying contaminated soil, sediment or sludge that may contain arsenic by adding iron, manganese, aluminum salts and Portland cement at dosages of 20 percent by weight and higher. Again, the process requires a curing period and has the additional disadvantage of high bulking after treatment. Hooykaas et al. use an oxidizing agent to oxidize organic matter, since it is difficult to solidify the waste matrix in the presence of organic matter. U.S. Pat. No. 5,252,003 (McGahan) discloses a process for controlling arsenic leaching from waste materials by adding iron (III) ions and magnesium (II) ions, preferably in the form of iron (III) sulfate and magnesium oxide.
U.S. Pat. No. 4,723,992 (Hager) discloses a process for fixing pentavalent arsenic in soil by adding metal salts or iron, aluminum, or chromium and a weak organic acid.
U.S. Pat. No. 5,130,051 (Falk) discloses a process for encapsulating waste that contains toxic metals, including arsenic, by adding a mixture of alkaline silicate and magnesium oxide, and, optionally, borax, a concentrated acid, a reducing agent, and fly ash at high dosage rates.
The iron (ferric) sulfate treatment process is ineffective against reduced forms of arsenic and does not provide long-term stability of treated wastes because, under certain natural conditions, the ferric ions may be reduced to ferrous form, thereby remobilizing the arsenic. The solidification processes require very high additive dosages with resultant high bulking of the treated waste.
None of the known technologies discloses a process for cost-effectively and permanently stabilizing arsenic in contaminated soil, sediment, or sludge where the arsenic can be present in trivalent and pentavalent states, and in both organic and inorganic forms.
The patents mentioned in the Background of the Invention are specifically incorporated herein by reference in their entirety.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a method for stabilizing an arsenic-contaminated waste matrix and reducing the leaching of arsenic to acceptable levels. A major objective of the invention is to provide a method for treating an arsenic-contaminated waste matrix that contains arsenic in both the reduced (arsenite) and/or the oxidized (arsenate) form. Other objectives of the invention include efficiently treating both organic and inorganic arsenic compounds, providing long-term, permanent treatment of arsenic, providing treatment with low bulking potential, and providing a treatment method that is cost-effective and easy to conduct.
In the method of the present invention, an agent for controlling oxidation-reduction (redox) potential (ORP), an agent for controlling pH, and an agent for adsorption and coprecipitation of the arsenic are mixed with the arsenic-contaminated material.
The sum of the amounts of added ORP control agent, pH control agent and adsorption-coprecipitation agent are insufficient to cause the waste matrix to solidify without adding a binding agent of the type identified by Hooykaas. The ORP control agent and the pH control agent are added in amounts that will vary with the amount of contaminants present, but in any event, in amounts sufficient to bring most (at least about 50%) of the contaminating arsenic into its higher oxidized state. The arsenite/arsenate transition is controlled by adjusting the redox potential and pH in a coordinated manner. For example, see Vance, D. B., “Arsenic: Chemical Behavior and Treatment,” National Environmental Journal 60-64 (May/June 1995), incorporated by reference herein in its entirety, which includes charts that depict the speciation of arsenic under various conditions. Agents for adsorbing and coprecipitating arsenic, such as ferric iron, are also known. Id. Although the chemicals used in the stabilization process can have a higher unit cost, the package cost is lower than that of solidification methods because the chemicals are used in small amounts. The ORP control agent, pH control agent and adsorption-coprecipitation agent can each be added to between 0.01 and 10 percent of the waste matrix, by weight.
The invention will be more fully understood upon consideration of the following detailed description.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
Not applicable.
DETAILED DESCRIPTION OF THE INVENTION
The invention describes a cost-effective, low-bulking, permanent method for stabilizing an arsenic-contaminated waste matrix wherein the method comprises the steps of incorporating an ORP control agent, a pH control agent, and an adsorption-coprecipitation agent. The types and additive rates of these component chemistries will depend on arsenic speciation and concentration, the waste matrix, and on the overall treatment objectives. A goal achieved by the method of the present invention is to bring the level of leachable arsenic to no higher than the maximum acceptable Toxicity Characteristic Leaching Procedure (TCLP) toxicity level of 5 mg/L dictated by RCRA. The same level would be set as the criterion for TCLP-arsenic in the proposed Universal Treatment Standard (UTS). The leachable arsenic as measured by the TCLP test can be reduced to a level below the maximum acceptable toxicity level of 5.0 mg/L, e.g., 0.5 mg/L, and perhaps lower.
The arsenic-contaminated materials can include, but are not limited to, sediment, soil, sludge and industrial wastes. The method is a low-bulking method, by which it is intended that after practicing the method the waste matrix volume is preferably no more than 10% greater, and more preferably no more than 5% greater, than before stabilization.
In a first embodiment of the method, each of the three agents is a separate class of chemical compound. In a second embodiment, a single chemical additive can act as two components in the treatment. An alternative would be that the chemical species added initially as one component of the chemistry may react with a waste matrix to produce a second component of the chemistry. In another embodiment, under suitable conditions, one chemical compound added to a specific waste matrix can serve the function of all three components in the disclosed arsenic stabilization method.
The ORP control agent can increase or decrease the redox potential of the waste matrix depending upon the arsenic speciation and presence of other metal contaminants. It is desirable to reduce the mobility by providing conditions where most (at least about 50%, preferably 60 to 95%, more preferably 80 to 95%) of the arsenic compounds are present in the higher oxidized (arsenate) state. For example, if a substantial fraction of arsenic is present in the arsenite form and no other major heavy metal oxy-anions are present in the waste, an oxidizing ORP agent is selected to increase the redox potential of the waste matrix.
This can be complicated by the presence of other heavy metal oxy-anions, such as hexavalent chromium, in the waste matrix. If the waste contains arsenic and another such heavy metal compound, the leaching potential of both the arsenic and the other heavy metal is decreased by lowering the redox potential of the waste matrix using a reducing ORP control agent. In this situation the ORP is reduced enough to convert chromium from its hexavalent state to less mobile trivalent state while the ORP would still be in the range for arsenic to be present most in its less mobile pentavalent state.
The oxidizing ORP control agent can be any compound that increases the redox potential of the waste matrix, although the compound is preferably one that has insignificant environmental impact upon the matrix. Suitable oxidizing ORP control agents include potassium permanganate, sodium chlorate, sodium perchlorate, calcium chlorite or another chlorinated oxidizing agent, sodium percarbonate, sodium persulfate, sodium perborate, potassium persulfate, hydrogen peroxide, magnesium peroxide, or another peroxide compound, compounds of multivalent elements at their higher oxidation state (e.g., ferric sulfate), gaseous oxygen, and ozone.
The reducing ORP control agents can be any compound that decreases the redox potential of the waste matrix, although the compound is preferably one that has insignificant environmental impact upon the matrix. Suitable reducing ORP control agents include ferrous sulfate, sulfur dioxide, sodium bisulfite, sodium metabisulfite, or the like.
In the presence of the adsorption-coprecipitation agent, the pH of the waste matrix controls the leaching potential of arsenic in conjunction with the redox potential of the waste. The pH control agent is selected to raise or lower the pH of the waste matrix depending on the original acidity/alkalinity of the waste and the treatment objectives, in accordance with the diagrams shown in Vance, supra. The pH control agents for raising pH can be any compound that raises the pH, without significant environmental impact, and can include magnesium oxide or hydroxide, calcium oxide or hydroxide, barium oxide or hydroxide, reactive calcium carbonate, sodium hydroxide, dolomitic lime, limestone (high calcium or dolomite), and the like.
The pH control agents for lowering pH can be any compound that lowers the pH, without significant environmental impact, and can include sulfuric acid, phosphoric acid, another mineral acid, or ferric sulfate, ferric chloride, aluminum sulfate, aluminum chloride, and like acidic compounds.
A suitable adsorption-coprecipitation agent can react with arsenic to form an insoluble arsenic compound or can immobilize arsenic on its surface by chemical adsorption. The adsorption-coprecipitation agent can be, but is not limited to, ferric sulfate, aluminum sulfate, activated alumina, or manganese dioxide.
The chemical additives, which can be in a solid state, aqueous slurry, or in solution, are thoroughly mixed with the waste matrix to be stabilized. The stabilization method can be performed in situ using conventional earth-moving equipment such as a back hoe, tiller, or drag line, or ex situ by blending the additives with the waste matrix in a mechanical device, such as a pugmill or a cement mixer. In a typical practice of the method for stabilizing arsenic and reducing arsenic leachability, the ORP control agent is mixed first with the waste matrix, followed by the adsorption-coprecipitation agent and then the pH control agent. Alternatively, all three components can be added simultaneously to, and mixed with, the waste matrix. The additive dosage requirements typically total less than 10-15 percent of the weight of the waste matrix. This is a major advantage over solidification methods, which require 20-30 percent or higher dosages of additives, including cement-like materials.
If the additives are mixed uniformly with the waste, no curing step is required. This is another significant advantage over solidification systems which typically requiring curing periods of one week or more.
The present invention will be more fully understood upon consideration of the following Examples which are intended to be exemplary and not limiting.
EXAMPLE 1
TABLE 1
Additive
(wt %)
Untreated
Treatment
ORP control
—
—
—
—
0.5
(potassium
permanganate)
pH control
—
—
1
1
1
(magnesium
oxide)
Ads/Coprecip
—
5
5
10
5
(ferric
sulfate)
TCLP (mg/L)
26.0
17.0
2.4
1.9
0.75
An arsenic-contaminated river sediment contained 14,000 mg/kg dry weight total arsenic and was determined to contain hazardous levels of arsenic, with a screening TCLP-arsenic concentration of 26.0 mg/L. The sediment was treated with a 3-component treatment chemistry according to the present invention. In this trial, shown in Table 1, the ORP control agent (potassium permanganate) was added at 0.5 percent by weight. The pH control agent (magnesium oxide) was added at 1 percent by weight. The adsorption-coprecipitation (Ads/Coprecip) agent (ferric sulfate) was added at 5 percent by weight. The sediment treated according to the invention was nonhazardous and had a screening TCLP-arsenic concentration of 0.75 mg/L.
In controls, ferric sulfate alone (5 percent by weight) reduced the screening TCLP-arsenic concentration to 17.0 mg/L, while magnesium oxide (1 percent by weight) with ferric sulfate (5 percent by weight) reduced the screening TCLP-arsenic concentration to 2.4 mg/L, respectively. At a higher dosage of ferric sulfate (10 percent by weight) with magnesium oxide (1 percent by weight), treatability of the sediment improved marginally, reducing the screening TCLP-arsenic concentration to 1.9 mg/L.
EXAMPLE 2
TABLE 2
Additive
(wt %)
Untreated
Treatment
ORP control
—
—
5
—
—
5
(potassium
permanganate)
pH control
—
5
—
—
5
5
(magnesium
oxide)
Ads/Coprecip
—
—
—
5
5
5
(ferric
sulfate)
TCLP (mg/L)
290
220
160
69
14.0
1.1
Arsenic-contaminated soil containing 10,100 mg/kg dry weight arsenic had a screening TCLP-arsenic concentration of 290 mg/L. This contaminated soil was treated with the additives described in Example 1, either singly or in combination. Separate treatment with 5 percent by weight dosages of potassium permanganate, magnesium oxide, or ferric sulfate gave screening TCLP-arsenic concentrations of 160 mg/L, 220 mg/L, and 69 mg/L, respectively. When magnesium oxide and ferric sulfate were mixed with the soil at 5 percent by weight each, the screening TCLP-arsenic concentration was reduced to 14.0 mg/L. When potassium permanganate, magnesium oxide, and ferric sulfate were added at 5 percent by weight each, the soil was rendered nonhazardous with a screening TCLP-arsenic concentration of 1.1 mg/L.
The present invention is not intended to be limited by the foregoing, but rather to encompass all such variations and modifications as come within the scope of the following claims.
|
A method for stabilizing arsenic in a waste matrix includes the steps of combining with the waste matrix an agent for controlling the oxidation-reduction potential of the matrix, an agent for controlling the pH of the matrix and an agent for adsorbing or coprecipitating the arsenic in the matrix.
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FIELD OF THE INVENTION
[0001] The invention relates to optical shutters and in particular to optical shutters based on semiconductor superlattice or multiple quantum well structures.
BACKGROUND OF THE INVENTION
[0002] Optical modulators based on semiconductor multiple quantum well (MQW) or superlattice (SL) structures are known.
[0003] An MQW structure comprises a stack of thin layers of narrow bandgap semiconductor material alternating with layers of wide bandgap semiconductor material so that each layer of narrow bandgap material is sandwiched between two layers of wide bandgap material. The alternating structure forms a series of quantum wells located in the narrow bandgap layers that are capable of confining conduction band electrons and valence band holes. Each narrow bandgap layer has a quantum well that confines conduction band electrons and a quantum well that confines holes in the valence band.
[0004] Width of the quantum wells in a narrow bandgap layer is substantially equal to the thickness of the narrow band layer. Generally, thickness of the narrow bandgap layers, and as a result, width of the quantum wells is substantially less than a diameter of an exciton that may be generated as an intermediate state when a photon excites an electron from the valence band to the conduction band of the narrow bandgap material. Depth of the electron quantum wells is substantially equal to a difference between bottoms of the conduction bands of the wide bandgap material and the narrow bandgap material. Depth of the hole quantum wells is substantially equal to a difference between tops of the valence bands of the wide bandgap and narrow bandgap materials.
[0005] In an MQW structure, depths of the quantum wells and thickness of the wide bandgap layers are such that a wave function of an electron or hole trapped in a quantum well of a narrow bandgap layer generally extinguishes rapidly in the wide bandgap layers on either side of the narrow bandgap layer. As a result, in an MQW structure, electrons and holes confined in quantum wells of a narrow bandgap layer are substantially isolated from electrons and holes confined in other narrow bandgap layers. Hereinafter, the wide bandgap layers are referred to as “barrier layers” and the narrow bandgap layers are referred to as “quantum well layers”.
[0006] When an electric field is applied perpendicular to the planes of the layers in an MQW structure, energy levels of allowed wave functions for trapped electrons and trapped holes in the quantum wells of a same quantum well layer are displaced towards each other. As a result, a minimum amount of energy required to transfer an electron from the valence band to the conduction band and produce thereby an electron-hole pair is reduced and the absorption spectrum of the MQW is red shifted. The red shift is a result of a quantum confined Stark effect that reduces a minimum amount of energy required to excite an electron-hole exciton as an intermediate state in raising an electron from the valence band to the conducting band. Changes, on the order of 10,000 cm −1 in an absorption coefficient for light having a wavelength, hereinafter an “operating wavelength”, near an absorption edge of an absorption spectrum of an MQW structure can be realized by red shifting the absorption spectrum.
[0007] U.S. Pat. No. 4,525,687, the disclosure of which is incorporated herein by reference, describes a small aperture MQW optical shutter comprising 50 GaAs narrow band quantum well layers sandwiched between wide bandgap barrier layers formed from Ga (1-x) Al x As with x˜0.36. The layers are formed in the intrinsic part of a pin diode. PCT Publication WO 99/40478, the disclosure of which is incorporated herein by reference, describes a wide aperture MQW high frequency optical modulator.
[0008] Performance of an MQW modulator is limited, inter alia, by an escape time for electrons and holes trapped in quantum wells of the MQW. Once holes and electrons are trapped in the MQW quantum wells of an MQW modulator after the modulator interacts with a beam of light, the electrons and holes require a finite escape time before they leave the quantum well region of the modulator. The same quantum wells that provide the modulating effects of an MQW modulator generally retard removal of the electrons and holes from the quantum wells. Buildup of photo-induced electrons and holes in quantum wells tends to shield and reduce effectiveness of electric fields applied to the MQW that are used to red shift the absorption spectrum of the modulator. In addition, current in the MQW layers generated by motion of the photo-induced electrons and holes in response to electric fields applied to the modulator can cause ohmic heating of the layers. The heating can result in an unwanted shift in the absorption edge of the modulator's absorption spectrum.
[0009] U.S. Pat. No. 5,210,428 to K. Goossen, the disclosure of which is incorporated herein by reference, notes that an article published in Applied Physics Letters, Vol. 57, No 22, pp suggests that escape times in an MQW modulator may be reduced by decreasing quantum well depth and barrier layer thickness. The patent describes an MQW modulator having a particular configuration of shallow quantum wells that results in reduced escape times. To provide the shallow quantum wells the effective bandgap energy of barrier layers in the modulator is chosen to be less than the sum of a longitudinal optical phonon energy and an exciton absorption energy in the modulator. U.S. Pat. No. 5,436,756 to W. H. Knox et. al. describes reducing current from photo-induced electrons in an MQW modulator by seeding the quantum well region of the modulator with non-radiative recombination centers such as protons.
[0010] A superlattice (SL) structure also comprises a series of quantum wells that are formed by a stack of quantum well layers sandwiched between barrier layers. However, in an SL, as distinguished from an MQW structure, widths of the barrier layers and heights of the quantum wells are such that wave functions of electrons and holes in quantum wells are not confined to individual quantum wells. There is substantial tunneling of electrons and holes between quantum wells. The wave functions in the quantum wells are relatively strongly coupled and in effect form extended wave functions that span substantially the full height of the stack of quantum well layers and have energies that form bands of allowed energies. When an electric field is applied to the SL perpendicular to the layers in the SL, coupling of wave functions between quantum wells is reduced and energies of allowed wave functions of electrons and holes in a same quantum well layer are displaced away from each other. The displacement is a result of narrowing of the widths of the energy bands defined by the allowed wave functions. As a result, a minimum amount of energy required to transfer an electron from the valence band of the quantum well layers to the conduction band in the quantum well layers is increased and the absorption spectrum of the MQW is blue shifted.
[0011] Optical modulators comprising SL structures are described in U.S. Pat. No. 5,194,983 to P. Voisin, the disclosure of which is incorporated herein be reference. Absorption spectra showing blue shifts for an SL structure having 4 nanometers thick layers are shown in the patent for different electric fields applied to the SL structure.
[0012] SLs in which absorption spectra of the SLs are red shifted are also possible. In “red shift” MQW modulators, red shifts that are used to modulate light are provided by changing energy differences of transitions, “direct transitions”, that occur between allowed electron and hole energy states in a same quantum well layer. “Oblique” transitions between allowed states of electrons and holes in quantum wells in adjacent quantum well layers of an SL provide an absorption spectrum that is red shifted by application of an electric field. However, red shifts provided by oblique transitions generally result in changes in absorption coefficients for light that are substantially smaller than changes in absorption coefficients provided by “direct” red shifts. In order to provide desired On/Off ratios, SL modulators that use oblique transitions to modulate light must generally provide relatively long path lengths for the light through quantum well layers of the SL. U.S. Pat. No. 5,073,809 to E. Bigan et. al., the disclosure of which is incorporated herein by reference, describes a “red shift SL” modulator in which a quantum well layer functions as a core of a waveguide having sufficient length to provide a suitable On/Off ratio.
[0013] Because barrier layers are relatively thin in SLs, escape times for photo-induced electrons and holes in SLs are relatively short and SLs are not as sensitive to escape times as are MQW modulators. However, changes in absorption coefficients for light at an operating wavelength of an SL are substantially smaller than changes in absorption coefficients achievable for light at an operating wavelength of an MQW modulator. On/Off transmission ratios for SLs are therefore generally substantially less than On/Off transmission ratios achievable with MQW modulators.
SUMMARY OF THE INVENTION
[0014] Aspects of some embodiments of the present invention relate to providing an optical multilayer semiconductor modulator having a relatively reduced escape time for photo-induced electrons and holes and an On/Off transmission ratio comparable to that achievable with prior art MQW modulators.
[0015] An aspect of some embodiments of the present invention relates to providing an optical multilayer semiconductor modulator having relatively reduced current generated by motion of photo-induced electrons and holes in electric fields applied to the modulator.
[0016] An aspect of some embodiments of the present invention relate to providing an optical multilayer semiconductor modulator having a relatively large On/Off ratio per unit length of the modulator along the modulator's optical axis, compared to prior art MQW modulators.
[0017] An optical modulator, in accordance with an embodiment of the present invention, comprises an SL structure having quantum well layers sandwiched between relatively thin barrier layers and a power supply that biases the SL structure at a bias voltage at which the modulator functions similarly to an MQW modulator.
[0018] The bias voltage, in accordance with an embodiment of the present invention, generates an electric field in the SL structure that substantially decouples allowed wave functions of electrons and holes in quantum wells of different quantum well layers of the modulator. As a result, in the biased modulator, allowed electron and hole wave functions in quantum wells of the modulator are confined similarly to the way in which electron and hole wave functions are confined in a prior art MQW modulator. The biased SL structure is then operated, in accordance with an embodiment of the present invention, similarly to the manner in which a prior art MQW modulator is operated. Voltage applied by the power supply to the modulator is increased above the bias voltage to generate a red shift in an absorption spectrum of the quantum well layer material of the modulator. The red shift causes a substantial increase in an absorption coefficient for light at an operating wavelength of the modulator. Hereinafter, the bias voltage used to decouple wave functions in an SL structure, in accordance with an embodiment of the present invention, is referred to as a “decoupling voltage”.
[0019] The inventors have found that changes in an absorption coefficient for light at an operating wavelength in quantum well material of a “decoupled SL modulator” operated as an MQW like modulator, in accordance with an embodiment of the present invention, can be substantially equal to changes in absorption coefficients of quantum well material achieved in prior art MQW modulators. In addition, because barrier layers comprised in the modulator are thinner than barrier layers in prior art MQW modulators, there is also more quantum well layer material per unit length along the modulator's optic axis than there is in prior art MQW modulators. Response of the quantum well material to voltage applied to an SL or MQW modulator substantially determines changes in absorption coefficient of light at the operating wavelength of the modulator. To the extent that a modulator comprises more quantum well material, an On/Off transmission ratio of the modulator generally increases. As a result, for a given voltage, On/Off transmission ratios for a modulator in accordance with an embodiment of the present invention, can often be equal to or greater than On/Off transmission ratios obtained with some prior art MQW modulators.
[0020] Because barrier layers in the modulator are thinner than barrier layers in prior art MQW modulators electron and hole escape times in the modulator are generally shorter than electron and hole escape times in prior art MQW modulators. In addition, when voltage applied to the modulator by the power supply is reduced below the decoupling voltage to a voltage at which wave functions in different quantum wells are “re-coupled”, the modulator operates as an SL structure having even shorter electron and hole escape times. In the presence of a moderate electric field, which is generated by an appropriate voltage below the decoupling voltage used to morph the SL structure to the MQW structure, photo-induced charges are rapidly swept out of the SL structure.
[0021] In some embodiments of the present invention, barrier layers in the modulator are seeded with non-radiative recombination traps, such as non-radiative recombination traps known in the art that are generated by growing the barrier layers at low temperature. Quantum well layers are not seeded with traps. At the trap sites photo-induced electrons recombine relatively rapidly with photo-induced holes in a non-radiative recombination process. As a result, the recombination traps function to substantially reduce lifetimes of photo-induced electrons and holes in the modulator. The traps thereby contribute to rapid removal of photo-induced electrons and holes and reduction of current resulting from motion of the electrons and holes in electric fields applied to the modulator.
[0022] In some embodiments of the present invention, all of the barrier layers are seeded with non-radiative recombination traps. However, seeding layers with traps can be an expensive process. The inventors have found that effective reductions in lifetimes of photo-induced electrons and holes can be achieved and costs of seeding a modulator reduced by seeding only some of the barrier layers, in accordance with an embodiment of the present invention. For example, the inventors have found that seeding only every fourth layer in a modulator in accordance with an embodiment of the present invention, can provide substantial savings in fabrication costs of the modulator while still providing effective reduction in lifetimes of photo-induced electrons and holes in the modulator.
[0023] It is noted that whereas methods of seeding layers, in accordance with an embodiment of the present invention, are described for modulators having an SL structure, the methods are applicable to heterojunction structures in general, whether they are SL structures or MQW structures.
[0024] There is therefore provided in accordance with an embodiment of the present invention, an optical modulator for modulating light comprising: a superlattice structure having a plurality of interleaved narrow and wide bandgap semiconductor layers, wherein wave functions of energy states of electrons and holes in different narrow bandgap layers are coupled; and a power supply that applies voltage to the superlattice structure between a first non-zero voltage and a second non-zero voltage to modulate the light.
[0025] Optionally, at the first voltage the wave functions are decoupled and the modulator has an absorption spectrum having an absorption edge determined by transitions between energy states in a same narrow bandgap layer. Optionally, at the second voltage the absorption edge is red shifted.
[0026] In some embodiments of the present invention, the optical modulator has an absorption spectrum having an absorption edge when zero voltage is applied by the power supply to the modulator and the absorption edge at the first voltage is blue shifted with respect to the absorption edge at zero voltage. Optionally, the absorption edge at the second voltage is red shifted with respect with respect to position of the absorption edge at the first voltage.
[0027] In some embodiments of the present invention, the second voltage is larger than the first voltage.
[0028] Optionally, following application of the second voltage, the power supply applies a voltage less than the first voltage to the modulator to remove electrons and holes generated therein by passage of the light therethrough.
[0029] In some embodiments of the present invention, substantially none of the narrow bandgap layers and at least one of the wide bandgap layers is seeded with non-radiative electron traps. Optionally, the at least one wide bandgap layers comprises all the wide bandgap layers. Optionally, the at least one wide bandgap layer comprises some but not all the wide bandgap layers. Optionally, the at least one wide bandgap layer comprises every other wide bandgap layer. Optionally, the at least one wide bandgap layer comprises every fourth wide bandgap layers. In some embodiments of the present invention the traps in a wide bandgap layer are generated by growing the wide bandgap layer at low temperature.
[0030] In some embodiments of the present invention, the thickness of the narrow bandgap layers is less than or equal to 10 nanometers. Optionally, the thickness of the narrow bandgap layers is substantially equal to 3 nanometers.
[0031] In some embodiments of the present invention, the thickness of the wide bandgap layers is less than or equal to 6 nanometers. Optionally, the thickness of the wide bandgap layers is substantially equal to 3 nanometers.
[0032] In some embodiments of the present invention, a ratio of thickness of a wide bandgap layer to a narrow bandgap layer is greater than or equal to one. Optionally, the ratio is greater than or equal to two. Optionally, the ratio is greater than or equal to three.
[0033] In some embodiments of the present invention, the number of narrow bandgap layers comprised in the superlattice structure is greater than 50. Optionally, the number of narrow bandgap layers comprised in the superlattice structure is substantially equal to 200. Optionally the number of narrow bandgap layers comprised in the superlattice structure is substantially equal to 300.
[0034] In some embodiments of the present invention, the superlattice structure is formed in an intrinsic region of a pin diode.
[0035] In some embodiments of the present invention, the first voltage is less than 30 volts. Optionally, the first voltage is less than 15 volts. Optionally, the first voltage is between 5 and 10 volts. Optionally, the first voltage is substantially equal to 25 volts. In some embodiments of the present invention, the second voltage is a voltage between 25-55 volts.
[0036] In some embodiments of the present invention, the narrow bandgap layers are formed form GaAs. In some embodiments of the present invention, the wide bandgap layers are formed from Al x Ga (1-x) As. Optionally, x is less than or equal to 0.7. Optionally, x is substantially equal to 0.3.
[0037] There is further provided in accordance with an embodiment of the present invention, a method of modulating intensity of a beam of light comprising: applying a non-zero voltage to a superlattice structure having a plurality of interleaved narrow and wide bandgap semiconductor layers so as to determine a transmittance for the light in the structure, wherein in the absence of voltage applied to the superlattice structure, wave functions of energy states of electrons and holes in different narrow bandgap layers are coupled; directing the light so that it is incident on the structure; and applying a second non-zero voltage different from the first voltage to the structure to change the transmittance and modulate thereby the light.
[0038] Optionally, at the first voltage the wave functions are decoupled and the modulator has an absorption spectrum having an absorption edge determined by transitions between energy states in a same narrow bandgap layer. Optionally, at the second voltage the absorption edge is red shifted with respect to position of the absorption edge at the first voltage
[0039] Alternatively or additionally, the absorption edge at the first voltage is blue shifted with respect to an absorption edge of an absorption spectrum that characterizes the modulator in the absence of voltage applied to the superlattice structure.
[0040] In some embodiments of the present invention, the second voltage is larger than the first voltage.
[0041] In some embodiments of the present invention, following application of the second voltage, a voltage less than the first voltage is applied to the modulator to remove electrons and holes generated therein by the passage of the light beam therethrough.
[0042] There is further provided in accordance with an embodiment of the present invention, an optical modulator comprising: a multilayer heterojunction structure comprising a plurality of interleaved narrow and wide bandgap semiconductor layers; and non-radiative traps located in at least one of the wide bandgap layers and substantially none of the narrow bandgap layers.
[0043] Optionally, the at least one wide bandgap layers comprises all the wide bandgap layers. Optionally, the at least one wide bandgap layer comprises some but not all the wide bandgap layers. Optionally, the at least one wide bandgap layer comprises every other wide bandgap layer. Optionally, the at least one wide bandgap layer comprises every fourth wide bandgap layers. In some embodiments of the present invention, the traps in a wide bandgap layer are traps generated by growing the wide bandgap layer at low temperature.
BRIEF DESCRIPTION OF FIGURES
[0044] Non-limiting examples of embodiments of the present invention are described below with reference to figures attached hereto. In the figures, identical structures, elements or parts that appear in more than one figure are generally labeled with the same numeral in all the figures in which they appear. Dimensions of components and features shown in the figures are chosen for convenience and clarity of presentation and are not necessarily shown to scale. The figures are listed below.
[0045] [0045]FIG. 1A schematically shows a cross sectional view of an optical modulator having an SL structure, in accordance with an embodiment of the present invention;
[0046] [0046]FIG. 1B is a graph of experimentally determined absorption edges showing a red shift following a blue shift for an optical modulator similar to the optical modulator shown in FIG. 1A, in accordance with an embodiment of the present invention;
[0047] [0047]FIG. 2A schematically shows wave functions and energy levels of allowed energy states of electrons and holes in quantum wells of the SL structure of the optical modulator shown in FIG. 1A in the absence of an electric field applied to the modulator, in accordance with an embodiment of the present invention;
[0048] [0048]FIG. 2B schematically shows allowed wave functions of electrons and holes in the SL structure of the modulator shown in FIGS. 1A and 2A and their energy levels, when a decoupling voltage is applied to the modulator; and
[0049] [0049]FIG. 2C schematically shows effects on electron and hole wave functions in the modulator shown in FIGS. 1 A, 2 A- 2 B when a voltage greater than the decoupling voltage is applied to the modulator.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0050] [0050]FIG. 1A shows a schematic cross section view of an optical modulator 20 in accordance with an embodiment of the present invention. Optical modulator 20 comprises an epitaxial superlattice, i.e. SL, structure 22 , formed between heavily p doped layer 24 and heavily n doped layer 26 . SL structure 22 and heavily doped layers 24 and 26 form a pin diode 28 . SL structure 22 comprises a plurality of narrow bandgap “quantum well” layers 30 alternating with wide bandgap barrier layers 32 . Only a few of quantum well layers 30 and barrier layers 32 are shown in FIG. 1A. It is noted that the words “narrow” and “wide” refer to bandgaps in layers 30 and 32 and not to thickness of the layers.
[0051] Narrow bandgap quantum well layers preferably have a thickness less than a diameter of an electron-hole exciton in the material of quantum well layers 30 . Typically, thickness of quantum well layers 30 is equal to or less than 10 nanometers. In order for electron and hole wave functions in different quantum well layers to be strongly coupled, preferably barrier layers 32 are substantially thinner than quantum well layers 30 .
[0052] Ohmic contact electrodes 34 and 36 , shown shaded, are provided on layers 24 and 26 respectively using methods known in the art. Electrodes 34 and 36 , as shown in FIG. 1A, are optionally formed in a shape of a “picture” frame having an open central region 38 . Central regions 38 of electrodes 34 and 36 define apertures of the modulator through which light enters and/or leaves modulator 20 . Various other types of contact electrodes, such as those described in above referenced PCT Publication WO 99/40478 referenced above, may be used in the practice of the present invention. Light that is modulated by modulator 20 is schematically represented by wavy arrows 21 shown entering and leaving modulator 20 .
[0053] In some embodiments of the present invention, barrier layers 32 are seeded with non-radiative traps, such as traps generated by growing the layers at low temperature. In some embodiments of the present invention, all barrier layers 32 are seeded with traps. However, seeding can be an expensive process. Therefore, in some embodiments of the present invention only some of barrier layers 32 are seeded. By seeding only some barrier layers rather than all barrier layers, cost of seeding for modulator 20 can be reduced. In FIG. 1A, only every fourth barrier layer 32 is seeded with traps, which are represented by circles 40 . Traps 40 serve as non-radiative recombination centers for photo-induced electrons and holes generated in modulator 20 and thus reduce their lifetime.
[0054] Modulator 20 comprises a power supply 50 that applies voltage to electrodes 34 and 36 to modify wave functions and energies of allowed electron and hole states in quantum wells of quantum well layers 30 . By modifying the energy levels of the allowed states, power supply 50 controls transmittance of modulator 20 to light at an operational wavelength of the modulator.
[0055] In accordance with an embodiment of the present invention, power supply 50 back biases pin diode 28 with a decoupling voltage, so as to decouple electron and hole wave functions in the quantum wells that are normally strongly coupled as a result of the SL structure of quantum well and barrier layers 30 and 32 . At the decoupling voltage, SL structure 22 has an absorption spectrum having an absorption edge that can be red shifted to modulate light at the operating wavelength of modulator 20 . In accordance with an embodiment of the present invention power supply 50 red shifts the absorption edge by increasing voltage applied to pin diode 28 above the decoupling voltage. As a result of the red shift, the absorption coefficient in material of quantum well layers 30 of modulator 20 increases and transmittance of the modulator decreases for light at the operational wavelength of the modulator.
[0056] Following a period during which the absorption edge of modulator 20 is red shifted and photo-induced electrons and holes are generated by light at an operational wavelength incident on the modulator, the electrons and holes recombine and/or drift out of SL structure 22 . The escape time of the electrons and holes is shorter than in prior art MQW modulators because barrier layers 32 are relatively thinner than barrier layers in prior art MQW modulators.
[0057] In addition, in some embodiments of the present invention, following a period during which the absorption edge is red shifted and photo-induced electrons and holes are generated, power supply 50 back biases pin diode 28 with a moderate voltage that is less than the decoupling voltage. At the reduced bias voltage the electron and hole wave functions in the quantum wells of quantum well layers 30 are “recoupled”. As a result, photo-induced electrons and holes that may be trapped in quantum wells of SL structure 22 are more easily able to tunnel between the quantum wells and are relatively rapidly swept out of SL structure 22 .
[0058] Preferably, the density of traps 40 in barrier layers 32 is such that an average effective recombination path length resulting from the traps for an electron or hole being swept out at the reduced voltage is substantially shorter than the width of superlattice structure 22 . As a result, substantially all electrons and holes that are being swept out at the reduced bias voltage are trapped and recombine in barrier layers 32 that are seeded with traps and do not reach electrodes 34 and 36 respectively.
[0059] The inventors have experimentally verified a red shift in a modulator, in accordance with an embodiment of the present invention, similar to modulator 20 . The modulator had an SL structure 22 comprising 280 quantum well layers 30 and 281 barrier layers 32 . Narrow gap layers 30 were formed from GaAs and wide gap layers 32 formed from Al x Ga (1-x) As with x˜0.3. Both narrow and wide bandgap layers 30 and 32 were about 3 nanometers thick, resulting in a total thickness for SL structure 22 of about 1.68 microns. The modulator had an operating wavelength at about 787.5 nanometers.
[0060] Electron and hole wave functions in the modulator are decoupled when power supply 50 applied a voltage of about 25 volts to the modulator. The red shift was observed for voltages above the decoupling voltage. FIG. 1B is a graph of experimentally determined absorption edges 120 , 121 and 122 for the modulator at 0 volts, 25 volts and 55 volts respectively. Absorption edge 121 obtained at 25 volts is blue shifted with respect to absorption edge 120 at 0 volts. Absorption edge 122 at 55 volts is red shifted with respect to both absorption edge 121 and absorption edge 120 . At voltages intermediate 25 and 55 volts, absorption edges are obtained that are red shifted with respect to absorption edge 121 less than the amount by which absorption edge 122 at 55 volts is red shifted. At an operating wavelength of 787.5 nanometers a difference between absorption edge 121 and absorption edge 122 , which is indicated by double arrowhead line 124 provides an On/Off transmission ration of about 4.
[0061] It is noted that modulators, in accordance with embodiments of the present invention, can have values for structural and operational parameters that are different from those given above. Decoupling voltages can be other than 25 volts, barrier layer thickness are not limited to thickness of about 3 nanometers and values of x other than 0.3 can be advantageous. Furthermore, modulators in accordance with embodiments of the present invention can have a number of quantum well layers that is more or less than 280 and provide On/Off ratios other than 4. Substantially any SL structure for which a decoupling voltage can be established and for which a voltage greater than the decoupling voltage red shifts an absorption edge of the SL structure can be used in the practice of the present invention.
[0062] Advantageous values for x are expected to be below 0.7 and advantageous thickness for barrier and quantum well layers are expected to be less than about 6 nanometers and 10 nanometers respectively. In addition, to increase On/Off transmission ratio per unit length along the axis of a modulator it is advantageous that quantum well layers have greater thickness than barrier layers. In some embodiments of the present invention a ratio of quantum well thickness to barrier layer thickness is greater than 2. In some embodiments of the present invention the ratio is greater than 3. Advantageous values for decoupling voltages are expected to be less than 30 volts. In some embodiments of the present invention a decoupling voltage is less than 15 volts. It is expected that an advantageous number of quantum well layers in a modulator in accordance with an embodiment of the present invention is equal to or greater than 50. In some embodiments of the present invention, the number of quantum well layers is greater than 200. In some embodiments of the present invention, the number of quantum, well layers is greater than 300.
[0063] For example, the inventors expect that a modulator similar to that used to provide the experimental results shown in FIG. 1B, but having narrow bandgap GaAs layers 30 about 8 nanometers thick instead of 3 nanometers thick, will have a decoupling voltage in a range from 5-10 volts. The decoupling voltage is reduced compared to the decoupling voltage in the “experimental modulator” because energy bands in the 8 nanometers narrow bandgap layers 30 (i.e. the quantum well layers) are narrower than those in the 3 nanometers quantum well layers of the experimental modulator. In addition, it is expected that as a result of the increased thickness of narrow bandgap GaAs layers 30 , that an On/Off transmission ratio for the modulator is expected to be about 20.
[0064] It is noted that whereas the above example of a modulator comprises a superlattice based on GaAs, superlattices comprised in modulators in accordance with embodiments of the present invention can be based on other III-V element combinations.
[0065] FIGS. 2 A- 2 C schematically illustrate effects of voltage applied to pin diode 28 by power supply 50 on energies and wave functions corresponding to lowest allowed energy states of electron and holes in quantum wells in SL structure 22 .
[0066] Each of FIGS. 2 A- 2 C shows a graph of the energy of the top of the valence band and the bottom of the conduction band in SL structure 22 as a function of position along a direction perpendicular to the planes of quantum well layers 30 and barrier layers 32 in the SL structure. In the graphs, direction perpendicular to the layers is referred to as the z-direction and displacement along the z-direction is measured in arbitrary units along the abscissa. Boundaries between quantum well and barrier layers 30 and 32 are indicated with dashed lines 60 . Energy, in arbitrary units is measured along the ordinate.
[0067] [0067]FIG. 2A schematically shows electron and hole quantum wells 62 and 64 respectively, which are formed in quantum well layers 30 of SL structure 22 as a result of differences in the bandgaps of quantum well layers 30 and barrier layers 32 . Energy of the top of the valence band in SL structure 22 as a function of z is indicated by a line 66 , which shows a difference in energy of the top of the valence band between quantum well layers 30 and barrier layers 32 . Energy of the bottom of the conduction band in SL structure 22 as a function of z is indicated by a line 68 , which shows a difference in energy of the bottom of conduction band between quantum well layers 30 and barrier layers 32 . A narrow bandgap of a quantum well layer 30 is indicated by arrowhead line 70 and a wide bandgap of an adjacent barrier layer 32 is indicated by an arrowhead line 72 .
[0068] In FIG. 2A power supply 50 does not apply a voltage difference between electrodes 34 and 36 of pin diode 28 and there is no electric field in SL structure 22 . Wave functions of allowed states of electrons in quantum wells 62 are strongly coupled and their energies form allowed energy bands for electron states in the SL structure. The wave functions at a given allowed energy in different quantum wells 62 are in resonance and “meld” together so that they appear as a single extended wave function that spans all the layers in SL structure 22 . Electrons tunnel relatively easily through barrier layers 32 and move relatively freely between quantum wells 62 in different quantum well layers 30 . As a result, the electrons are able to move relatively freely within substantially all the volume of SL structure 22 .
[0069] Amplitude of “melded” wave functions of a lowest allowed energy state of electrons in quantum wells 62 is schematically represented by width of a shaded band 74 shown in FIG. 2A. An energy band of SL structure 22 determined by lowest energy states of the quantum wells is schematically represented in FIG. 2A by a shaded band 76 . Width of band 76 represents an energy spread of the states that define the energy band. Similarly, wave functions of holes in quantum wells 64 are strongly coupled and define energy bands of allowed states of holes in quantum wells 64 . Holes are also able to move relatively freely within substantially all the volume of SL structure 22 . (Though, because of their greater effective mass, generally, the holes are more sluggish and tend to be more confined by the quantum well structure than electrons.) Amplitude of coupled wave functions as a function of z of a lowest energy state for holes in quantum wells 64 is schematically represented by width of a shaded band 78 . A shaded band 80 represents an energy band of the lowest energy states of the holes in quantum wells 64 .
[0070] In the absence of an applied electric field, a minimum amount of energy “Eo” equal to an energy difference between the top of band 80 and the bottom of band 76 is required to raise an electron from the valence band to the conduction band of modulator 20 . A double arrowhead line labeled with the minimum energy Eo indicates graphically the minimum energy required to raise an electron to the conduction band.
[0071] In FIG. 2B power supply 50 applies a decoupling bias voltage between electrodes 34 and 36 , in accordance with an embodiment of the present invention. The decoupling voltage generates an electric field “go” in SL structure 22 that modifies the shape of quantum wells 62 and 64 and decouples wave functions of electron and hole states in different quantum wells. Direction of electric field ε o is indicated by the direction of a block arrow labeled by ε o and potential energy increases in the positive z direction. As a result of the applied field ε o electron states in adjacent quantum wells 62 are shifted out of resonance. The electron wave functions are decoupled and become relatively localized to regions of quantum wells 62 . In addition, widths of energy bands (e.g. widths of energy bands 76 and 80 shown in FIG. 2A) of wave functions in quantum wells 62 decrease and each energy band becomes an energy level with well defined energy.
[0072] Amplitude of “confined” electron wave functions for electrons in lowest energy states of quantum wells 62 are schematically represented by tapered bands 90 located in the quantum wells. Energy levels of of the lowest electron energy states in quantum wells 62 are schematically represented by lines 92 .
[0073] Hole wave functions are similarly decoupled and confined to regions of quantum wells 64 and hole energy bands converge to energy levels in the presence of go. Amplitude of confined hole wave functions for holes in lowest energy states of quantum wells 64 are schematically represented by tapered bands 94 located in the quantum wells. Energy levels of the lowest hole energy states in quantum wells 64 are schematically represented by lines 96 .
[0074] An energy difference between the centers of a hole energy band 76 and an electron energy band 80 in a same quantum well layer shown in FIG. 2A is substantially the same as an energy difference between corresponding energy levels 92 and 96 shown in FIG. 2B. However, an energy difference between the top of energy band 76 and the bottom of energy band 80 in FIG. 2A is slightly less than an energy difference between energy levels 92 and 96 . As a result, slightly more energy is required to raise an electron to the conduction band when power supply 50 applies a decoupling voltage to pin diode 28 and as in prior art there is a blue shift in the absorption spectrum of modulator 20 . A minimum energy ε 1 , which is greater than Eo is now required to raise an electron to the conduction band in modulator 20 in the presence of electric field o. A double arrowhead line labeled with ε 1 indicates graphically the minimum energy ε 1 .
[0075] In FIG. 2C power supply 50 applies a voltage to pin diode 28 that is greater than the decoupling voltage to generate and electric field ε 1 >ε o in SL structure 22 , in accordance with an embodiment of the present invention. Electric field ε 1 operates on wave functions 90 and 94 in modulator 20 that are already confined to their respective quantum wells 30 and have their energy bands reduced to energy levels by electric field go. The inventors have found that an effect of the increase of electric field from ε o to ε 1 on the energy levels of the confined lowest energy states of quantum wells 62 and 64 is similar to the quantum confined Stark effect generated by an electric field in an MQW modulator. An electron energy level 92 in a quantum well 62 shown in FIG. 2B is shifted towards lower energies and moves closer to the bottom of the quantum well (i.e. the bottom of the conduction band in the quantum well layer in which the quantum well is located). Similarly, an energy level 96 for holes in a quantum well 64 shown in FIG. 2B is shifted towards lower energies and moves closer to the top of the quantum well. (It is to be noted that energy of hole states decreases towards the top of the valence band and when energy of a hole state approaches the top of the valence band the hole state approaches the bottom of its quantum well.) The shifted energy levels resulting from the increase in electric field from ε o to ε 1 are schematically shown as energy levels 100 and 102 in FIG. 2C.
[0076] The shifting of energy bands 92 and 96 that “transform” energy levels 92 and 96 into energy levels 100 and 102 respectively reduce a minimum energy required to raise an electron from the valence band to the conduction band of a quantum well layer 30 . The minimum energy is equal to an energy difference, ε 2 <ε 1 , between energy level 102 and energy level 100 in the layer. Energy difference ε 2 is shown graphically in FIG. 2C by a double arrowhead line labeled by ε 2 .
[0077] As a result of the reduction in energy required to raise an electron to the conduction band of a quantum well layer 30 the absorption spectrum of modulator 20 is red shifted. The inventors have found that the red shift, in accordance with an embodiment of the present invention, can provide an On/Off transmission ratio for light at the operational wave length of modulator 20 that substantially approaches or exceeds On/Off ratios achieved by some prior art MQW modulators.
[0078] In the description and claims of the present application, each of the verbs, “comprise” “include” and “have”, and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of members, components, elements or parts of the subject or subjects of the verb.
[0079] The present invention has been described using detailed descriptions of embodiments thereof that are provided by way of example and are not intended to limit the scope of the invention. The described embodiments comprise different features, not all of which are required in all embodiments of the invention. Some embodiments of the present invention utilize only some of the features or possible combinations of the features. Variations of embodiments of the present invention that are described and embodiments of the present invention comprising different combinations of features noted in the described embodiments will occur to persons of the art. The scope of the invention is limited only by the following claims.
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Provided is an optical modulator for modulating light comprising: a superlattice structure having a plurality of interleaved narrow and wide bandgap semiconductor layers, wherein wave functions of energy states of electrons and holes in different narrow bandgap layers are coupled; and a power supply that applies voltage to the superlattice structure between a first non-zero voltage and a second non-zero voltage to modulate the light.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims benefit of the filing date of the copending U.S. Provisional Application No. 60/327,674 (filed Oct. 5, 2001), hereby incorporated by reference.
FIELD OF THE INVENTION
The invention relates to the treatment of immunoinflammatory disorders.
BACKGROUND OF THE INVENTION
Immunoinflammatory disorders (e.g., rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, stroke-induced brain cell death, ankylosing spondylitis, fibromyalgia, and inflammatory dermatoses, asthma, multiple sclerosis, type I diabetes, systemic lupus erythematosus, scleroderma, systemic sclerosis, and Sjögren's syndrome) are characterized by dysregulation of the immune system and inappropriate activation of the body's defenses, resulting in damage to healthy tissue.
One percent of humans world-wide are afflicted with rheumatoid arthritis (RA), a relentless, progressive disease causing severe swelling, pain, and eventual deformity and destruction of joints. According to the Arthritis Foundation, rheumatoid arthritis currently affects over two million Americans, of which women are three times more likely to be afflicted. Rheumatoid arthritis is characterized by inflammation of the lining of the joints and/or other internal organs, and the presence of elevated numbers of lymphocytes and high levels of proinflammatory cytokines.
Diagnosis of RA generally includes: (i) morning stiffness in joints lasting at least one hour before improvement, (ii) arthritis of three or more joint areas having simultaneously soft tissue swelling or fluid; (iii) arthritis of at least one hand joint; (iv) symmetric arthritis, i.e., simultaneous involvement of the same joint area on both sides of the body; (v) rheumatoid nodules; (vi) abnormal serum rheumatoid factor; and (vii) radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints. Patients are classified as having RA if at least four of these seven criteria, and (i) through (iv) must have been present for at least six weeks. (American College of Rheumatology, 1987 Criteria for the Classification of Acute Arthritis of Rheumatoid Arthritis, based on Arnett F C et al., Arthritis Rheum. 1988; 31:315-324). Pain per se is not required for the diagnosis of RA.
Treatment of RA generally includes anti-inflammatory strategies directed at suppressing the clinical manifestations of joint inflammation, including synovial thickening, joint tenderness, and joint stiffness. Drugs used to address these signs and symptoms generally include (i) non-steroidal anti-inflammatory drugs (NSAIDs; e.g., detoprofen, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenameate, mefenamic acid, meloxicam, nabumeone, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, rofecoxib, aspirin, choline salicylate, salsalte, and sodium and magnesium salicylate)—these drugs may be adequate for mild RA, but do not appear to alter the longterm course of the disease; and (ii) steroids (e.g., cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone).
Treatment for RA may also include strategies directed at limiting the long term joint damage and deformity caused by the inflammation in the joints. Such treatments are generally described as DMARDs, i.e., disease modifying antirheumatic drugs (e.g., cyclosporine, azathioprine, methotrexate, leflunomide, cyclophosphamide, hydroxychloroquine, sulfasalazine, D-penicillamine, minocycline, gold, etanercept (soluble TNF receptor) and infliximab (a chimeric monoclonal anti-THF antibody)).
There is a need to develop new regimens for the treatment of immunoinflammatory disorders.
SUMMARY OF THE INVENTION
We have discovered that the combination of tetra-substituted pyrimidopyrimidines, such as dipyridamole (also known as 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido(5,4-d)pyrimidine), and corticosteroids, such as fludrocortisone (as known as 9-alpha-fluoro-11-beta, 17-alpha, 21-trihydroxy-4-pregnene-3,20-dione acetate), and prednisolone (also known as 1-dehydrocortisol; 1-dehydrohydrocortisone; or 1,4-pregnadiene-11beta, 17alpha,21-triol-3,20-dione; or 11beta,17alpha,21-trihydroxy-1,4-pregnadiene-3,20-dione), brings about substantial suppression of TNFα levels induced in peripheral blood mononuclear cells (PBMCs).
Accordingly, the invention features, in one aspect, a method for treating a patient who has, or who is at risk for developing, an immunoinflammatory disorder. The method includes administering (i) a corticosteroid; and (ii) a tetra-substituted pyrimidopyrimidine having the formula (I):
wherein each Z and each Z′ is, independently, N, O, C,
When Z or Z′ is O or
then p=1, when Z or Z′ is N,
then p=2, and when Z or Z′ is C, then p=3. In formula (I), each R 1 is, independently, X, OH, N-alkyl (wherein the alkyl group has 1 to 20, more preferably 1-5, carbon atoms); a branched or unbranched alkyl group having 1 to 20, more preferably 1-5, carbon atoms; or a heterocycle, preferably as defined in formula (Y), below. Alternatively, when p>1, two R 1 groups from a common Z or Z′ atom, in combination with each other, may represent —(CY 2 ) k — in which k is an integer between 4 and 6, inclusive. Each X is, independently, Y, CY 3 , C(CY 3 ) 3 , CY 2 CY 3 , (CY 2 ) 1-5 OY, substituted or unsubstituted cycloalkane of the structure C n Y 2n−1 , wherein n=3-7, inclusive. Each Y is, independently, H, F, Cl, Br, or I. In one embodiment, each Z is the same moiety, each Z′ is the same moiety, and Z and Z′ are different moieties. The two compounds are each administered in an amount that, when combined with the second compound, is sufficient to treat or prevent the immunoinflammatory disorder.
In a related aspect, the invention features a method for suppressing the production of one or more proinflammatory cytokines in a patient in need thereof by administering to the patient (i) a corticosteroid; and (ii) a tetra-substituted pyrimidopyrimidine having formula (I).
In particularly useful tetra-substituted pyrimidopyrimidines in both aspects of the invention, R 1 is a substituted or unsubstituted furan, purine, or pyrimidine, (CH 2 CH 2 OY), (CH 2 CH(OH)CH 2 OY), (HCH 2 CH(OH)CX 3 ), ((CH 2 ) n OY), where n=2-5,
In other useful tetra-substituted pyrimidopyrimidines, each Z is N and the two associated R 1 groups combine in the form of —(CH 2 ) 5 —, and each Z′ is N and each Z′-associated R 1 group is —CH 2 CH 2 OH.
The tetra-substituted pyrimidopyrimidine and the corticosteroid may be present in pharmaceutical compositions that contain a pharmaceutically acceptable carrier, diluent, or excipient, and are administered at dosages and frequencies sufficient to suppress TNFα levels enough to produce a therapeutic benefit to the patient. The tetra-substituted pyrimidopyrimidine and the corticosteroid can be administered within 14 days of each other (e.g., within 10 days, within five days, twenty-four hours, or one hour of each other, or even simultaneously). Administration of each compound can occur, e.g., 1 to 5 times each day, or as necessary to alleviate symptoms.
Accordingly, this invention also features pharmaceutical compositions, pharmaceutical packs, and kits containing one or more tetra-substituted pyrimidopyrimidine and one or more corticosteroid. The methods and compositions (pharmaceutical compositions and pharmaceutical packs) of the invention may feature higher order combinations of tetra-substituted pyrimidopyrimidines and corticosteroids. Specifically, one, two, three, or more tetra-substituted pyrimidopyrimidines may be combined with one, two, three, or more corticosteroids. In preferred embodiments, the tetra-substituted pyrimidopyrimidine, the corticosteroid, or both are approved by the United States Food and Drug Administration (USFDA) for administration to a human.
Exemplary tetra-substituted pyrimidopyrimidines that are useful in the methods and compositions of this invention include 2,6-disubstituted 4,8-dibenzylaminopyrimido[5,4-d]pyrimidines. Particularly useful tetra-substituted pyrimidopyrimidines include dipyridamole (also known as 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido(5,4-d)pyrimidine), mopidamole, dipyridamole monoacetate, NU3026 (2,6-di-(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxy-4,8-di-piperidinopyrimidopyrimidine), NU3059 (2,6-bis-(2,3-dimethyoxypropoxy)-4,8-di-piperidinopyrimidopyrimidine), NU3060 (2,6-bis[N,N-di(2-methoxy)ethyl]-4,6-di-piperidinopyrimidopyrimidine), and NU3076 (2,6-bis(diethanolamino)-4,8-di-4-methoxybenzylaminopyrimidopyrimidine).
The invention described herein has been exemplified using the corticosteroids fludrocortisone; however, a skilled artisan will recognize that structural and functional analogs of these corticosteroids can also be used in combination with the tetra-substituted pyrimidopyrimidines in the methods and compositions of the present invention. Other useful corticosteroids may be identified based on the shared structural features and mechanism of action among the corticosteroid family.
The tetra-substituted pyrimidopyrimidine and the corticosteroid may be administered in the same or different pharmaceutical formulations. Pharmaceutical compositions or components of the pharmaceutical pack may be administered by the same or different routes and include oral, rectal, intravenous, intramuscular, subcutaneous, intra-articular, inhalation, topical or transdermal, vaginal, and ophthalmic administration.
Dosages of the tetra-substituted pyrimidopyrimidine and the corticosteroid may be determined individually. In prior art therapeutic regimines, tetra-substituted pyrimidopyrimidine are typically administered to human patients at about 0.5-800 mg/day, 18-600 mg/day, or 50-400 mg/day. Corticosteroids are typically administered at about 0.1-1500 mg/day, 0.5-30 mg/day, or 0.5-10 mg/day. Low doses of corticosteroids (e.g., 10 mg/day or less of prednisolone, or its equivalent) are preferred. In the methods and compositions of the invention, both components typically will be used in lower dosages than those given above, because the two drugs operate together to treat or suppress the subject disorder. Thus, the pyrimidopyrimidine can be used, according to the invention, at a dosage of 0.5-50 mg/day, and the corticosteroid can be used at a dosage of 0.1 to 10 mg/day. The total daily dosage of the tetra-substituted pyrimidopyrimidine and the corticosteroid may be administered in one, two, three, four, or more dosages. It is not necessary for the tetra-substituted pyrimidopyrimidine and the corticosteroid to be administered in the same number of daily doses. Further, there is no need for the tetra-substituted pyrimidopyrimidine and/or the corticosteroid to be administered every day or by the same route of administration. For example, the tetra-substituted pyrimidopyrimidine may be administered by intravenous injection every second day and the corticosteroid administered by topical application twice every day. Accordingly, when administered in different compositions, pharmaceutical formulations, packs, and kits are prepared in form and dosage suitable for achieving the desired treatment regimen.
The diseases or disorders treated using the methods and compositions of this invention are immunoinflammatory disorders including, for example, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, stroke-induced brain cell death, ankylosing spondylitis, fibromyalgia, asthma, multiple sclerosis, type I diabetes, systemic lupus erythematosus, scleroderma, systemic sclerosis, inflammatory dermatoses, or Sjögren's syndrome.
The invention also features a method for identifying compounds useful for treating a patient having an immunoinflammatory disorder. The method includes the steps of: contacting immune cells in vitro with (i) an immunomodulatory compound selected from the group of a tetra-substituted pyrimidopyrimidine having formula (I) or a corticosteroid; and (ii) a candidate compound, and determining whether the immune response is modulated relative to (a) immune cells contacted with the immunomodulatory compound but not contacted with the candidate compound, and (b) immune cells contacted with the candidate compound but not with the immunomodulatory compound. A candidate compound that, when combined with an immunomodulatory compound, modulates the immune response to a greater degree than controls, is a compound that is potentially useful for treating a patient having an immunoinflammatory disorder.
Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs thereof, as well as racemic mixtures of the compounds described herein.
By “heterocycle” is meant any cyclic molecule, wherein one or more of the ring atoms is an atom other than carbon. Preferable heterocycles consist of one or two ring structures. Preferable heteroatoms are N, O, and S. Each ring structure of the heterocycle consists of 3-10 atoms, preferably 4-8 atoms, and most preferably 5-7 atoms. Each ring structure need not contain a heteroatom, provided that a heteroatom is present in at least one ring structure. Preferred heterocycles are, for example, beta-lactams, furans, tetrahydrofurans, pyrroles, pyrrolidines, thiophenes, tetrahydrothiophenes, oxazoles, imidazolidine, indole, guanine, and phenothiazine.
By “patient” is meant any animal (e.g., a human).
The term “immunoinflammatory disorder” encompasses a variety of conditions, including autoimmune diseases. Immunoinflammatory disorders result in the destruction of healthy tissue by an inflammatory process. Examples of immunoinflammatory disorders include, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, stroke-induced brain cell death, ankylosing spondylitis, fibromyalgia, asthma, multiple sclerosis, type I diabetes, systemic lupus erythematosus, scleroderma, systemic sclerosis, inflammatory dermatoses, myasthenia gravis, and Sjögren's syndrome.
By “corticosteroid” is meant any naturally occurring or synthetic steroid hormone which can be derived from cholesterol and is characterized by a hydrogenated cyclopentanoperhydrophenanthrene ring system. Naturally occurring corticosteroids are generally produced by the adrenal cortex. Synthetic corticosteroids may be halogenated. Functional groups required for activity include a double bond at Δ4, a C3 ketone, and a C20 ketone. Corticosteroids may have glucocorticoid and/or mineralocorticoid activity. In preferred embodiments, the corticosteroid is either fludrocortisone or prednisolone.
Exemplary corticosteroids include algestone, 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 6-alpha-methylprednisolone 21-acetate, 6-alpha-methylprednisolone 21-hemisuccinate sodium salt, 6-alpha,9-alpha-difluoroprednisolone 21-acetate 17-butyrate, amcinafal, beclomethasone, beclomethasone dipropionate, beclomethasone dipropionate monohydrate, 6-beta-hydroxycortisol, betamethasone, betamethasone-17-valerate, budesonide, clobetasol, clobetasol propionate, clobetasone, clocortolone, clocortolone pivalate, cortisone, cortisone acetate, cortodoxone, deflazacort, 21-deoxycortisol, deprodone, descinolone, desonide, desoximethasone, dexamethasone, dexamethasone-21-acetate, dichlorisone, diflorasone, diflorasone diacetate, diflucortolone, doxibetasol, fludrocortisone, flumethasone, flumethasone pivalate, flumoxonide, flunisolide, fluocinonide, fluocinolone acetonide, 9-fluorocortisone, fluorohydroxyandrostenedione, fluorometholone, fluorometholone acetate, fluoxymesterone, flupredidene, fluprednisolone, flurandrenolide, formocortal, halcinonide, halometasone, halopredone, hyrcanoside, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone probutate, hydrocortisone valerate, 6-hydroxydexamethasone, isoflupredone, isoflupredone acetate, isoprednidene, meclorisone, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, paramethasone, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone metasulphobenzoate, prednisolone sodium phosphate, prednisolone tebutate, prednisolone-21-hemisuccinate free acid, prednisolone-21-acetate, prednisolone-21(beta-D-glucuronide), prednisone, prednylidene, procinonide, tralonide, triamcinolone, triamcinolone acetonide, triamcinolone acetonide 21-palmitate, triamcinolone diacetate, triamcinolone hexacetonide, and wortmannin. Desirably, the corticosteroid is fludrocortisone or prednisolone.
By “an effective amount” is meant the amount of a compound, in a combination of the invention, required to treat or prevent an immunoinflammatory disease. The effective amount of active compound(s) used to practice the present invention for therapeutic treatment of conditions caused by or contributing to an inflammatory disease varies depending upon the manner of administration, the age, body weight, and general health of the patient. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an effective amount.
By the term “cytokine suppressing amount” is meant an amount of the combination which will cause a decrease in the vivo presence or level of the proinflammatory cytokine, when given to a patient for the prophylaxis or therapeutic treatment of an immunoinflammatory disorder which is exacerbated or caused by excessive or unregulated proinflammatory cytokine production.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
DETAILED DESCRIPTION
We have discovered that the combination of a tetra-substituted pyrimidopyrimidine with a corticosteroid substantially has substantial TNFα suppressing activity against stimulated white blood cells. The combinations of dipyridamole with fludrocortisone, and dipyridamole with prednisolone were particularly effective. Thus, the combination of a tetra-substituted pyrimidopyrimidine with a corticosteroid is useful for the treatment of immunoinflammatory disorders.
Dipyridamole
Dipyridamole (2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido(5,4-d)pyrimidine) is a tetra-substituted pyrimidopyrimidine that is used as a platelet inhibitor, e.g., to prevent blood clot formation following heart valve surgery and to reduced the moribundity associated with clotting disorders, including myocardial and cerebral infarction. Typically, anticoagulation therapy (prophylaxis or treatment) is effected by administering dipyridamole at about 75-200 mg b.i.d, t.i.d., or q.i.d. either alone or in combination with aspirin. In the invention, lower doses generally can be used, e.g., 20-80 mg, administered by any of the prior art routes.
Tetra-substituted Pyrimidopyrimidines
Tetra-substituted pyrimidopyrimidines are structural analogs that can replace dipyridamole in the methods and compositions of this invention. Tetra-substituted pyrimidopyrimidines generally are of formula (I), above.
Therapy
Combination therapy according to the invention may be performed alone or in conjunction with another therapy and may be provided at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital. Treatment generally begins at a hospital so that the doctor can observe the therapy's effects closely and make any adjustments that are needed. The duration of the combination therapy depends on the type of immunoinflammatory disorder being treated, the age and condition of the patient, the stage and type of the patient's disease, and how the patient responds to the treatment. Additionally, a person having a greater risk of developing an immunoinflammatory disorder (e.g., a person who is genetically predisposed or previously had an immunoinflammatory disorder) may receive prophylactic treatment to inhibit or delay an inflammatory response.
The dosage, frequency and mode of administration of each component of the combination can be controlled independently. For example, one compound may be administered orally three times per day, while the second compound may be administered intramuscularly once per day. Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recovery from any as yet unforeseen side-effects. The compounds may also be formulated together such that one administration delivers both compounds.
Formulation of Pharmaceutical Compositions
The administration of each compound of the combination may be by any suitable means that results in a concentration of the compound that, combined with the other component, is antiinflammatory upon reaching the target region. The compound may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
Pharmaceutical compositions according to the invention may be formulated to release the active compound substantially immediately upon administration or at any predetermined time or time period after administration. The latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create a substantially constant concentration of the drug within the body over an extended period of time; (ii) formulations that after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time; (iii) formulations that sustain drug action during a predetermined time period by maintaining a relatively, constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance (sawtooth kinetic pattern); (iv) formulations that localize drug action by, e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ; and (v) formulations that target drug action by using carriers or chemical derivatives to deliver the drug to a particular target cell type.
Administration of compounds in the form of a controlled release formulation is especially preferred in cases in which the compound, either alone or in combination, has (i) a narrow therapeutic index (i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; in general, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD50) to median effective dose (ED50)); (ii) a narrow absorption window in the gastro-intestinal tract; or (iii) a very short biological half-life so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.
Any of a number of strategies can be pursued in order to obtain controlled release in which the rate of release outweighs the rate of metabolism of the compound in question. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Thus, the drug is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
Solid Dosage Forms for Oral Use
Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.
The tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period. The coating may be adapted to release the active drug substance in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active drug substance until after passage of the stomach (enteric coating). The coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose). Furthermore, a time delay material such as, e.g., glyceryl monostearate or glyceryl distearate may be employed.
The solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, (e.g., chemical degradation prior to the release of the active drug substance). The coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology, supra.
The two drugs may be mixed together in the tablet, or may be partitioned. In one example, the first drug is contained on the inside of the tablet, and the second drug is on the outside, such that a substantial portion of the second drug is released prior to the release of the first drug.
Formulations for oral use may also be presented as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
Controlled Release Oral Dosage Forms
Controlled release compositions for oral use may, e.g., be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance.
Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
A controlled release composition containing one or more of the compounds of the claimed combinations may also be in the form of a buoyant tablet or capsule (i.e., a tablet or capsule that, upon oral administration, floats on top of the gastric content for a certain period of time). A buoyant tablet formulation of the compound(s) can be prepared by granulating a mixture of the drug(s) with excipients and 20-75% w/w of hydrocolloids, such as hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose. The obtained granules can then be compressed into tablets. On contact with the gastric juice, the tablet forms a substantially water-impermeable gel barrier around its surface. This gel barrier takes part in maintaining a density of less than one, thereby allowing the tablet to remain buoyant in the gastric juice.
Liquids for Oral Administration
Powders, dispersible powders, or granules suitable for preparation of an aqueous suspension by addition of water are convenient dosage forms for oral administration. Formulation as a suspension provides the active ingredient in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents are, for example, naturally-occurring phosphatides (e.g., lecithin or condensation products of ethylene oxide with a fatty acid, a long chain aliphatic alcohol, or a partial ester derived from fatty acids) and a hexitol or a hexitol anhydride (e.g., polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate, and the like). Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, sodium alginate, and the like.
Parenteral Compositions
The pharmaceutical composition may also be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, or the like) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. The formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulation. Formulations can be found in Remington: The Science and Practice of Pharmacy, supra.
Compositions for parenteral use may be provided in unit dosage forms (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added (see below). The composition may be in form of a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation, or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. Apart from the active drug(s), the composition may include suitable parenterally acceptable carriers and/or excipients. The active drug(s) may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release. Furthermore, the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, and/or dispersing agents.
As indicated above, the pharmaceutical compositions according to the invention may be in the form suitable for sterile injection. To prepare such a composition, the suitable active drug(s) are dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate). In cases where one of the compounds is only sparingly or slightly soluble in water, a dissolution enhancing or solubilizing agent can be added, or the solvent may include 10-60% w/w of propylene glycol or the like.
Controlled Release Parenteral Compositions
Controlled release parenteral compositions may be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, or emulsions. Alternatively, the active drug(s) may be incorporated in biocompatible carriers, liposomes, nanoparticles, implants, or infusion devices. Materials for use in the preparation of microspheres and/or microcapsules are, e.g., biodegradable/bioerodible polymers such as polygalactin, poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamnine) and, poly(lactic acid). Biocompatible carriers that may be used when formulating a controlled release parenteral formulation are carbohydrates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, or antibodies. Materials for use in implants can be non-biodegradable (e.g., polydimethyl siloxane) or biodegradable (e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters)).
Rectal Compositions
For rectal application, suitable dosage forms for a composition include suppositories (emulsion or suspension type), and rectal gelatin capsules (solutions or suspensions). In a typical suppository formulation, the active drug(s) are combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols and polvoxyethylene sorbitan fatty acid esters. Various additives, enhancers, or surfactants may be incorporated.
Compositions for Inhalation
For administration by inhalation, typical dosage forms include nasal sprays and aerosols. In a typically nasal formulation, the active ingredient(s) are dissolved or dispersed in a suitable vehicle. The pharmaceutically acceptable vehicles and excipients (as well as other pharmaceutically acceptable materials present in the composition such as diluents, enhancers, flavoring agents, and preservatives) are selected in accordance with conventional pharmaceutical practice in a manner understood by the persons skilled in the art of formulating pharmaceuticals.
Percutaneous and Topical Compositions
The pharmaceutical compositions may also be administered topically on the skin for percutaneous absorption in dosage forms or formulations containing conventionally non-toxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes. The formulations include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters, and other kinds of transdermal drug delivery systems. The pharmaceutically acceptable carriers or excipients may include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gel-forming agents, ointment bases, perfumes, and skin protective agents.
Examples of emulsifying agents are naturally occurring gums (e.g., gum acacia or gum tragacanth) and naturally occurring phosphatides (e.g., soybean lecithin and sorbitan monooleate derivatives). Examples of antioxidants are butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, butylated hydroxy anisole, and cysteine. Examples of preservatives are parabens, such as methyl or propyl p-hydroxybenzoate, and benzalkonium chloride. Examples of humectants are glycerin, propylene glycol, sorbitol, and urea. Examples of penetration enhancers are propylene glycol, DMSO, triethanolamine, N,N-dimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone and derivatives thereof, tetrahydrofurfuryl alcohol, and AZONE™. Examples of chelating agents are sodium EDTA, citric acid, and phosphoric acid. Examples of gel forming agents are CARBOPOL™, cellulose derivatives, bentonite, alginates, gelatin and polyvinylpyrrolidone. Examples of ointment bases are beeswax, paraffin, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids (Span), polyethylene glycols, and condensation products between sorbitan esters of fatty acids and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate (TWEEN™)).
The pharmaceutical compositions described above for topical administration on the skin may also be used in connection with topical administration onto or close to the part of the body that is to be treated. The compositions may be adapted for direct application or for introduction into relevant orifice(s) of the body (e.g., rectal, urethral, vaginal or oral orifices). The composition may be applied by means of special drug delivery devices such as dressings or alternatively plasters, pads, sponges, strips, or other forms of suitable flexible material.
Controlled Release Percutaneous and Topical Compositions
There are several approaches for providing rate control over the release and transdermal permeation of a drug, including: membrane-moderated systems, adhesive diffusion-controlled systems, matrix dispersion-type systems, and microreservoir systems. A controlled release percutaneous and/or topical composition may be obtained by using a suitable mixture of the above-mentioned approaches.
In a membrane-moderated system, the active drug is present in a reservoir which is totally encapsulated in a shallow compartment molded from a drug-impermeable laminate, such as a metallic plastic laminate, and a rate-controlling polymeric membrane such as a microporous or a non-porous polymeric membrane (e.g., ethylene-vinyl acetate copolymer). The active compound is only released through the rate-controlling polymeric membrane. In the drug reservoir, the active drug substance may either be dispersed in a solid polymer matrix or suspended in a viscous liquid medium such as silicone fluid. On the external surface of the polymeric membrane, a thin layer of an adhesive polymer is applied to achieve an intimate contact of the transdermal system with the skin surface. The adhesive polymer is preferably a hypoallergenic polymer that is compatible with the active drug.
In an adhesive diffusion-controlled system, a reservoir of the active drug is formed by directly dispersing the active drug in an adhesive polymer and then spreading the adhesive containing the active drug onto a flat sheet of substantially drug-impermeable metallic plastic backing to form a thin drug reservoir layer. A matrix dispersion-type system is characterized in that a reservoir of the active drug substance is formed by substantially homogeneously dispersing the active drug substance in a hydrophilic or lipophilic polymer matrix and then molding the drug-containing polymer into a disc with a substantially well-defined surface area and thickness. The adhesive polymer is spread along the circumference to form a strip of adhesive around the disc.
In a microreservoir system, the reservoir of the active substance is formed by first suspending the drug solids in an aqueous solution of water-soluble polymer, and then dispersing the drug suspension in a lipophilic polymer to form a plurality of microscopic spheres of drug reservoirs.
Dosages
The dosage of each compound of the claimed combinations depends on several factors, including: the administration method, the condition to be treated, the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect the dosage used.
As described above, the compound in question may be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories. Parenteral administration of a compound is suitably performed, for example, in the form of saline solutions or with the compound incorporated into liposomes. In cases where the compound in itself is not sufficiently soluble to be dissolved, a solubilizer such as ethanol can be applied. Below, for illustrative purposes, the dosages for dipyridamole and fludrocortisone are described.
Routes of Administration
For oral, intramuscular, subcutaneous, topical, inhalation, rectal, vaginal and ophthalmic administration of the tetra-substituted pyrimidopyrimidine, the dosage used according to the invention is about 0.5-800 mg/day, preferably about 5-600 mg/day, 10-100 mg/day, and more preferably 0.5-50 mg/day. Administration can be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases. In some cases of serious illness, up to 1600 mg/day may be necessary. For intravenous administration of the tetra-substituted pyrimidopyrimidine, the dosage used is about 0.1-200 mg/day, preferably about 0.5-150 mg/day, 1-100 mg/day, and more preferably about 0.5-50 mg/day. Administration can be one to four times daily. Systemic dosing will result in steady-state plasma concentrations preferably of 0.1-7.0 μM, more preferably, 0.5-5.0 μM, and most preferably, 1.0-2.0 μM.
The dosage of the corticosteroid for use in combination with the tetra-substituted pyrimidopyrimidine is about 0.1-1500 mg/day, preferably about 0.5-30 mg/day, and more preferably about 0.1-10 mg/day. Administration can be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases. In cases of serious illness, dosages up to 3000 mg/day may be necessary.
The following examples are to illustrate the invention. They are not meant to limit the invention in any way.
EXAMPLE 1
Preparation of Pairwise Compound Mixed Combination Serial Dilution Matrix
Stock solutions at 16 mg/ml of dipyridamole, and 1.6 mg/ml of fludrocortisone acetate (Sigma-Aldrich, St. Louis, Mo.; catalog numbers D9766 and F6127, respectively) were made in dimethylsulfoxide (DMSO). The dipyridamole master plates were made by adding 25 μl of the concentrated stock solution to columns 3, 9, and 15 (rows C through N) of a polypropylene 384-well storage plate that had been pre-filled with 75 μl of anhydrous DMSO. Using a TomTec Quadra Plus liquid handler, the 25 μl of dipyridamole stock solution was serially diluted four times into the adjacent columns (columns 4-7, 10-13, 16-19). The sixth column (8, 14, and 20) did not receive any compound and served as a vehicle control. The fludrocortisone master plates were made by adding 25 μl of the concentrated stock solution to the appropriate wells (row C, columns 3-8; row C, columns 9-14; row C, columns 15-20; row I, columns 3-8; row I, columns 9-14; row I, columns 15-20) of the appropriate master polypropylene 384-well storage plate. These master plates had been pre-filled with 75 μl of anhydrous DMSO. Using the TomTec Quadra Plus liquid handler, the 25 μl was serially diluted four times in the adjacent rows (rows D-G, and J-M). The sixth row (H and N) did not receive any compound to serve as a vehicle control. Master plates were sealed and stored at −20 C. until ready for use.
The final dipyridamole/fludrocortisone combination plates were generated by transferring 1 μl from each of the dipyridamole and fludrocortisone master plates to a dilution plate containing 100 μl of media (RPMI; Gibco BRL, #11875-085), 10% Fetal Bovine Serum (Gibco BRL, #25140-097), 2% Penicillin/Streptomycin (Gibco BRL, #15140-122)) using the TomTec Quadra Plus liquid handler. This dilution plate was then mixed and a 10 μl aliquot transferred to the final assay plate, which had been pre-filled with 40 μl/well RPMI media containing the appropriate stimulant to activate TNFα secretion (see below).
EXAMPLE 2
Assay for TNFα Suppressing Activity by the Combination of Dipyridamole and Fludrocortisone
The compound dilution matrix was assayed using a TNFα ELISA method. Briefly, a 100 μl suspension of diluted human white blood cells contained within each well of a polystyrene 384-well plate (NalgeNunc) was stimulated to secrete TNFα by treatment with a final concentration of 10 ng/ml phorbol 12-myristate 13-acetate (Sigma) and 750 ng/μl ionomycin (Sigma). Various concentrations of each test compound were added at the time of stimulation. After 16-18 hours of incubation at 37° C. in a humidified incubator, the plate was centrifuged and the supernatant transferred to a white opaque polystyrene 384 well plate (NalgeNunc, Maxisorb) coated with an anti-TNF antibody (PharMingen, #18631D). After a two-hour incubation, the plate was washed (Tecan PowerWasher 384) with phosphate buffered saline (PBS) containing 0.1% Tween 20 (polyoxyethylene sorbitan monolaurate) and incubated for an additional one hour with another anti-TNF antibody that was biotin labeled (PharMingen, 18642D) and horseradish peroxidase (HRP) coupled to strepavidin (PharMingen, #13047E). After the plate was washed with 0.1% Tween 20/PBS, the HRP substrate (which contains luminol, hydrogen peroxide, and an enhancer such as para-iodophenol) was added to each well and light intensity measured using a LJL Analyst luminometer. Control wells contained a final concentration of 1 μg/ml cyclosporin A (Sigma).
Together, dipyridamole and fludrocortisone were able to suppress TNFα secretion in blood stimulated with phorbol 12-myristate 13-acetate and ionomycin. As seen in Tables 1 and 2, dipyridamole was able to enhance the potency of fludrocortisone by 60-fold. At a concentration of 947 nM, fludrocortisone alone inhibited TNFα secretion by 39%. Addition of 124 nM dipyridamole to a concentration of only 15 nM fludrocortisone resulted in the inhibition of TNFα secretion by 39% (Table 1). Efficacy was maintained while reducing the total drug species by over 80%, from 947 nM to 163 nM. In the presence of 2 μM dipyridamole, 50% TNFα inhibition is achieved by only 4 nM fludrocortisone. This level of inhibition is not possible with fludrocortisone alone at concentrations that would be expected to cause serious mineralocorticoid-induced side effects. Dipyridamole enhancement of fludrocortisone activity was observed in a secondary screen (Table 2). Again, a low dose of 495 nM dipyridamole enhanced the potency of fludrocortisone by over 135 fold. Specifically, 947 nM fludrocortisone alone was required to achieve a 52% reduction of TNFα secretion. A similar reduction (49%) was measured for the combination of 7 nM fludrocortisone and 495 nM dipyridamole. Further, the addition of 248 nM dipyridamole resulted in a supramaximal effect on the inhibition of TNFα secretion at fludrocortisone concentrations as low as 59 nM.
TABLE 1
Primary Screen Data of Fludrocortisone vs
Dipyridamole Average Result of 2 Plates
(% TNFα suppression from P/I-induced white blood cells)
Fludro-
cortisone
Dipyridamole [μM]
[μM]
7.927
1.982
0.495
0.124
0.031
0.000
0.947
82.90
66.61
54.90
52.48
61.35
39.19
0.237
81.88
61.99
52.35
52.11
46.77
36.66
0.059
79.57
60.37
47.08
45.47
42.93
32.49
0.015
77.13
54.06
40.70
38.73
30.62
22.63
0.004
74.61
50.60
34.21
24.90
22.52
17.21
0.000
66.37
35.24
13.21
9.08
3.68
0.00
TABLE 2
Secondary Screen Data of Fludrocortisone vs
Dipyridamole Average Result of 2 Plates
(% TNFα Suppression from P/I-induced white blood cells)
Fludro-
cortisone
Dipyridamole [μM]
[μM]
7.927
3.964
1.982
0.991
0.495
0.248
0.124
0.062
0.031
0.000
0.947
89.12
82.25
78.01
69.10
67.91
61.77
60.82
53.38
53.41
52.05
0.473
92.64
84.40
78.44
70.25
65.06
60.25
56.14
53.68
50.07
50.16
0.237
89.69
83.68
82.01
70.36
66.53
65.46
60.90
56.65
52.34
49.25
0.118
87.58
80.66
76.13
68.18
65.89
67.09
58.91
54.17
47.39
46.42
0.059
84.43
79.37
73.86
64.53
63.88
58.96
56.84
48.63
44.66
40.24
0.030
88.61
76.42
68.58
65.77
62.08
51.31
49.96
47.02
44.19
36.95
0.015
90.46
79.36
73.52
65.22
56.39
62.88
43.17
47.73
46.00
37.77
0.007
84.11
75.29
69.74
64.61
48.90
42.05
38.92
39.27
36.70
29.49
0.004
79.02
75.15
65.79
55.19
46.00
41.93
35.15
30.94
30.20
22.40
0.000
78.11
66.54
62.36
48.20
33.73
23.02
12.13
9.43
10.16
−3.50
EXAMPLE 3
Preparation of Pairwise Compound Mixed Combination Serial Dilution Matrix
A compound matrix of dipyridamole and prednisolone were prepared according to the method of Example 1. The initial stock solution of dipyridamole was 16 mg/ml, and prednisolone was 1.6 mg/ml.
EXAMPLE 4
Assay for TNFα Suppressing Activity by the Combination of Dipyridamole and Prednisolone
The compound dilution matrix of Example 3, was assayed using the TNFα ELISA method of Example 2. The results are shown in Table 3. Together, dipyridamole and prednisolone were able to suppress TNFα secretion in blood stimulated with phorbol 12-myristate 13-acetate and ionomycin to a greater extent than either compound alone. Specifically, dipyridamole greatly increased the potency of prednisolone. Prednisolone alone, at a concentration of 250 nM, can suppress TNFα secretion by 38%. The same level of suppression (41%) can be achieved by only 1 nM prednisolone in combination with 2 μM dipyridamole. This represents a shift in the potency of prednisolone of over 250-fold. Further, the addition of 2 μM dipyridamole to 250 nM prednisolone resulted in a supramaximal effect (57%), compared to prednisolone alone (38%). The combination of low doses of prednisolone and dipyridamole, therefore, results in the inhibition TNFα to levels previously unattainable without a high risk of glucocorticoid-induced side effects.
TABLE 3
Primary Screen Data of Prednisolone vs
Dipyridamole Average Result of 2 Plates
(% TNFα suppression from P/I-induced white blood cells)
Prednisolone
Dipyridamole [μM]
[μM]
7.93
1.98
0.50
0.12
0.031
0.00
0.250
70.30
56.72
48.90
50.82
46.08
38.25
0.063
68.53
57.68
51.61
47.24
37.57
33.00
0.016
66.48
45.20
40.12
40.99
32.42
37.84
0.004
61.06
47.25
34.66
33.48
32.42
19.99
0.001
57.35
40.84
32.10
25.47
20.64
4.86
0.000
47.51
27.21
18.30
12.63
11.24
0.00
OTHER EMBODIMENTS
Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific desired embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the fields of medicine, immunology, pharmacology, endocrinology, or related fields are intended to be within the scope of the invention.
All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually incorporated by reference.
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The invention features a method for treating a patient having an immunoinflammatory disorder, by administering to the patient (i) a tetra-substituted pyrimidopyrimidine, and (ii) a corticosteroid simultaneously or within 14 days of each other in amounts sufficient to reduce or inhibit immunoinflammation.
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FIELD OF THE INVENTION
[0001] The invention relates to the field of dairy-derived food ingredients. In particular, it relates to an improved milk powder for use as a food ingredient, and a method of preparing same.
BACKGROUND TO THE INVENTION
[0002] Modern technology has allowed the fractionation of milk into its individual components, which are valued and used for their intrinsic functional benefits. In particular, ultra-filtration and other membrane based technologies have been used to manufacture high protein milk protein concentrates (MPC's) and whey protein concentrates (WPC's). The manufacture of these products results in the generation of significant quantities of permeates, a large proportion of which are disposed of at cost to the manufacturer, or utilised in relatively low value applications such as lactose extraction or stock feed manufacture.
[0003] Total world production of MPC's and WPC's is significant and growing. It is estimated that this results in the generation of 1.5 million metric tonnes of permeate solids. Lactose may be extracted from these permeate solids, but the low commercial returns for lactose renders this operation at marginal financial feasibility at best. In addition, this would still leave approximately 30% of the feed solids as lactose mother liquor, which is typically dumped at a cost to the manufacturer.
[0004] The dumping of the 1.5 million metric tonnes of permeate solids produced also tends to create environmental problems.
[0005] In addition, lower protein milk powders known in the prior art tend to have poorer functionality, particularly in relation to flavour profile. It would be advantageous to provide lower protein milk powders which perform as well as standard milk powders.
[0006] Consequently, it is an object of the present invention to provide a method of deriving commercially viable products from otherwise ‘waste’ permeate solids.
SUMMARY OF THE INVENTION
[0007] According to its broadest aspect, the invention provides a method for the processing of milk ultrafiltration permeate created during the manufacture of milk protein concentrate (MPC) and/or whey protein concentrate (WPC) to produce a reduced-protein milk powder, which nevertheless has useful functional and sensory properties.
[0008] In particular, by combining said permeate with a volume of skim or whole milk, it has been found possible to prepare a reduced-protein milk powder for a range of different applications which surprisingly deliver the required functionality at a lower cost than traditional milk powders.
[0009] However, the ability to produce modified milk powders with significantly lower protein content in conventional milk powder plants is limited by the hygroscopic nature of the amorphous lactose in the milk, which adversely affects the drying process of the powder due to the higher effective content of lactose in the drying feedstock. Thus, there is a need for an improved process to produce these modified milk powders, which alleviates this problem.
[0010] According to another aspect of the invention, there is provided a method for the production of modified milk powder, said method including the steps of:
[0011] preparing a standardised milk (skimmed, semi-skimmed or full cream);
[0012] concentrating in an evaporator to total solids of around 50% by weight;
[0013] cooling in a controlled manner to achieve partial crystallisation of the lactose; and
[0014] then spray drying the crystallised concentrate.
[0015] Crystallising a portion of the lactose in the modified milk powder before drying allows a modified milk concentrate with as little as 6% protein (dry non-fat matter basis) to be dried without adversely affecting the quality of the powder.
[0016] According to another aspect of the invention, there is provided a reduced-protein milk powder, preferably having a protein content of less than 25% by weight dry non-fat matter, which has enhanced functional performance in the preparation of food products, as obtained by the method described above. Using the method described above, it is possible to provide a reduced-protein milk powder a protein content as low as 6% by weight dry non-fat matter.
[0017] The inventors have surprisingly found that milk powders with significantly reduced protein levels, as obtained via the inventive method, can perform as well as standard milk powders (which typically have a protein content of at least 34% of non-fat dry matter) in at least some applications. Further, the inventors have also found that such powders perform better than blends of milk powder and lactose.
[0018] The advantage provided by the invention is the ability to spray dry a modified milk concentrate containing between 6% and 25% protein on a dry non-fat basis.
[0019] For example, according to the invention, fresh skim milk may be standardised to a desired protein to solids-non-fat level, typically about 10 to 12%. This standardisation is generally carried out by adding the appropriate amount of milk permeate to the fresh skimmed milk. This can also be done by composing suitable liquid milks from fresh whole milk, partially skimmed milk, cream, butterfat, buttermilk, lactose, etc.
[0020] The milk may then be partially demineralised, or alternatively, one of the feed streams may be partially demineralised. This may be done by nano-filtration, ion exchange or any of the other technologies known to those skilled in the art. The modified milk is then subjected to a heat treatment for pasteurisation. The heat treated milk is then fed into an evaporator and concentrated to around 50% by weight, but preferably 55% by weight total solids.
[0021] The concentrate is then cooled, in a controlled manner, to crystallise a portion of the lactose. Once adequate crystallisation of the lactose has occurred, spray drying of the concentrate can be carried out preferably with a rotary disc atomiser to introduce the partially crystallised concentrate to the drier.
[0022] The further processing of the milk powder after the atomisation step comprising drying, cooling, storage and packing is then completed according to the standard known to experts in the field.
[0023] It is also expected that a similar result could be obtained by mixing crystallised milk permeate with concentrated milk solids before drying, cooling and packing as described above. Further, this technology could also be used to produce fat-filled milk powders and even non-dairy milk powder replacers from permeates.
[0024] According to another aspect of the invention, there is provided a method for the production of modified full cream milk powder, said method including the steps of:
[0025] preparing a standardised milk;
[0026] concentrating in an evaporator to total solids of around 50% by weight;
[0027] cooling in a controlled manner to achieve partial crystallisation of the lactose;
[0028] blending the crystallised concentrate with homogenised cream in such a ratio as to ensure the finished product composition, and;
[0029] then spray drying the crystallised concentrate blend.
[0030] The above method is preferred where production of a full-cream milk powder is desired.
[0031] According to another aspect of the invention, there is provided a reduced protein skim milk powder manufactured according to the process as defined above.
[0032] According to another aspect of the invention, there is provided a reduced protein full cream milk powder manufactured according to the process as defined above.
[0033] According to another aspect of the invention, there is provided the use of reduced protein milk powders as described above in the manufacture of food products.
[0034] According to another aspect of the invention, there are provided commercially prepared food products resulting from the use described above.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0035] The invention will now be described by way of a specific, non-limiting example. In the following examples, parts and percentages are by weight unless otherwise specified.
Example 1
Preparation of Reduced Protein Skim Milk Powder
[0036] In preparing a modified milk powder according to the invention, 26,066 kg of skim milk containing 3.73% protein, 0.11% fat and 9.26% non-fat solids was mixed with 97,618 kg of waste milk permeate containing 0.33% protein, 0.02% fat and 8.81% non-fat solids to form 123,684 kg of modified milk with 1.04% protein, 0.04% fat and 8.91% non-fat solids.
[0037] The mixture was passed by a centrifugal pump through the pre-heater of an evaporator where it was heated to a temperature of 80° C. and held for 5 seconds before passing into the first effect of a multiple effect falling film evaporator.
[0038] After being concentrated to 53% total solids the concentrate was cooled to 32° C. through a plate heat exchanger and filled into a crystalliser (25,000 L capacity, supplied by APV Australia), where it was further cooled down to 10° C. over a period of 12 hours.
[0039] The crystallised concentrate was then spray dried to produce 11,231 kg of modified milk powder containing 11.5% protein, 0.4% fat and 1.5% moisture. The powder was then cooled and packed.
Example 2
Preparation of Reduced Protein Full Cream Milk Powder
[0040] In preparing a modified full cream milk powder according to the invention, 4,334 kg of crystallised concentrate (prepared according to Example 1) containing 5.94% protein, 0.14% fat and 53.0% total solids was mixed with 2,206 kg of homogenised cream (homogenised at 40 Bar) containing 1.90% protein, 40.0% fat and 5.52% non-fat solids to form 6,540 kg of modified full cream milk concentrate. This concentrate contained 4.58% protein, 13.58% fat and 50.48% total solids.
[0041] The crystallised concentrate was then spray dried to produce 3,351 kg of modified full cream milk powder containing 8.93% protein, 26.5% fat and 1.5% moisture. The powder was then cooled and packed.
Example 3
Use of Reduced Protein SMP in UHT Milk
[0042] A 12.5% protein milk powder, prepared according to the process described in Example 1, was screened in UHT milk formulations. As a control, recombined milk was prepared from whole milk powder (WMP), having 3.5% fat, 12.5% total solids and 3.21% protein. A stabiliser (Degussa XSA BN325) was added at 0.4%.
[0043] The mix was heat treated in an UHT process at 138° C. for 3 seconds, cooled to 70° C., homogenised at 150 bar (single stage homogeniser), and cooled to 30° C. Samples were refrigerated immediately after collection.
[0044] Three further batches were prepared, replacing WMP solids with a milk powder prepared according to Example 1 and anhydrous milk fat (AMF) to produce a similar composition to the control milk. WMP solids substitution was made at 10%, 20% and 30% of total solids. The corresponding protein levels were calculated to be 3.00%, 2.82% and 2.61% at these substitution rates. The milks were processed with the same conditions as the control. Each of the samples then underwent informal sensory evaluation.
[0045] Very few discernable differences were found between samples. Almost all tasters had a preference for the 30% replacement product, which was judged to have a slightly sweeter flavour.
[0046] There were no differences in the thickness and mouth-feel characteristics of the four milks, indicating a successful use of the product according to the invention in milk.
Example 4
Use of Reduced Protein SMP in Flavoured UHT Milk
[0047] Following the results of the above Example 3 trials using 12.5% protein permeate powder in UHT milk formulations, further trials were undertaken looking at manufacturing flavoured milks with SMP replacement up to 70% of non-fat solids.
[0048] For this trial, a typical vanilla malt flavoured milk formulation was prepared. Milk was recombined from whole milk powder (WMP) at 3.5% fat, 12.5% total solids and 3.21% protein. Sugar, flavour and stabiliser premix was added as per a typical vanilla malt flavoured milk formulation familiar to those skilled in the art.
[0049] The formulation was heat treated in a UHT process at 100° C. for 3 seconds, cooled to 70° C., homogenised at 100 & 50 Bar (in a two stage homogenisation process), and cooled to 30° C.
[0050] Three further batches were prepared, replacing WMP solids with a milk powder prepared according to Example 1 and AMF to produce a similar composition to the control. WMP solids substitution was made at 30%, 50% and 70%. The protein levels were calculated to be 2.35%, 1.56%, 1.08% and 0.59% for the different rates of substitution. The modified milks were processed with the same conditions as the control. Each of the samples then underwent informal sensory evaluation.
[0051] Very few discernable differences were found between the samples at up to 50% substitution. The 70% substitution sample did have a slightly different mouth feel and some tasters felt there was some mineral aftertaste compared with the lower substitution samples. However as a stand alone product, the milk was still judged to be very acceptable.
Example 5
Use of Reduced Protein SMP in Flavoured Milk
[0052] Five flavoured milks were then prepared using typical fresh flavoured milk flavours and formulations familiar to those skilled in the art. For each flavour, a control was prepared using fresh whole milk, along with a test batch with 50% of the non-fat solids replaced by a milk powder prepared according to Example 1 (MPC11). Cream was added to normalise the fat level in the test batch. The milks so prepared were pasteurised at 80° C. for 15 secs, homogenised at 100 & 50 Bar in a two stage homogenisation process and cooled to 6° C. The flavours prepared were Vanilla Malt, Chocolate, Coffee, Strawberry and Banana.
[0053] Samples were evaluated informally for organoleptic properties. There were general comments made by the testers that the samples with MPC11 added and flavoured with vanilla malt, chocolate and coffee had more body and/or a creamier mouth-feel. The flavour intensity also seemed to be slightly higher in the products with MPC 11 added. No such differences were noted with the strawberry and banana flavoured milks.
Example 6
Use of Reduced Protein SMP (RPSMP) in White and Chocolate Flavoured UHT Milk
[0054] Further trials of UHT milk were run with RPSMP replacing 50% of the non-fat solids. These included four white milk formulations and four chocolate flavoured milk formulations. The white milk formulations were:
1. A control made from WMP with 0.02% carrageenan added. 2. Milk with 50% of the non-fat solids replaced with High Ash RPSMP with cream added to adjust the fat level. 3. Milk with 50% of the non-fat solids replaced with Low Ash RPSMP with cream added to adjust the fat level. 4. Milk with the same protein level as the RPSMP milks made with lactose and with cream added to adjust the fat level.
[0059] Analyses of the white milk formulations are given in the table below:
[0000]
2. 50% High
3. 50% Low
White Milk
1. Control
Ash
Ash
4. Lactose
Total Solids %
12.49
12.56
12.69
12.77
Fat %
3.71
3.67
3.69
3.89
Lactose %
5.1
6.3
6.3
6.6
Phosphorus %
0.09
0.079
0.083
0.058
Chloride %
0.09
0.11
0.10
0.06
[0060] The flavour testing results, by informal evaluation of cold products were:
Control: Slightly powdery with good creaminess and mouth feel. 50% High Ash: Clean and good mouth feel and good flavour. No powdery taste. 50% Low Ash: Similar to high ash product. 50% Lactose: Sweeter than others. Thin and lacking body.
[0065] For the chocolate milk evaluation, four milks were produced.
1. A control made from WMP with an added chocolate premix, supplied by International Flavours and Fragrances under item no. SN498212, included at 5.32 g/L. 2. Milk with 50% of the non-fat solids replaced with High Ash RPSMP with cream added to adjust the fat level. 3. Milk with 50% of the non-fat solids replaced with Low Ash RPSMP with cream added to adjust the fat level. 4. Milk with the same protein level as the RPSMP milks made with lactose and with cream added to adjust the fat level.
[0070] Analyses of the chocolate milk formulations are given in the table below:
[0000]
2. 50% High
3. 50% Low
Chocolate Milk
1. Control
Ash
Ash
4. Lactose
Total Solids %
16.96
17.02
17.12
17.07
Fat %
3.45
3.4
3.41
3.53
Lactose %
4.9
6.0
5.9
6.1
Phosphorus %
0.087
0.076
0.078
0.055
Chloride %
0.08
0.11
0.11
0.05
[0071] The flavour testing results, by informal evaluation of cold products were;
Control: Thick and good chocolate flavour. 50% High Ash: Good mouth feel. Very good natural chocolate flavour. The chocolate flavour was enhanced and was well balanced 50% Low Ash: Similar to high ash product. 50% Lactose: Thin and lacking mouth feel. Slightly artificial chocolate flavour. Not balanced.
Example 7
Use of Reduced Protein Skim Milk Powder (RPSMP) in Milk Chocolate
[0076] A trial was run to assess the suitability of an RPSMP prepared in accordance with Example 1, as well as a Skim Milk Powder (SMP)/Lactose blend, in a milk chocolate application. In these trials, three chocolate samples were prepared and examined. These were identified as:
1. Control (100% SMP) 2. 100% replacement of SMP with RPSMP 3.67% replacement of SMP with Lactose.
[0080] Each of the chocolates manufactured was assessed in terms of ease of processing and handling, final product colour, Casson plastic viscosity, yield value, particle size, hardness, snap and organoleptic attributes.
[0081] The base milk chocolate formulation for 25 kg batches of each of the three above chocolates is shown in the table below.
[0000]
Trial 1:
Trial 2:
Trial 3:
SMP Control
RPSMP
SMP/Lactose
Ingredient
%
(kg)
(kg)
Blend (kg)
Castor Sugar
43
10.75
10.75
10.75
Cocoa Butter
21
5.25
5.25
5.25
Cocoa Liquor
11.5
2.875
2.875
2.875
SMP
17.7
4.425
1.46
(5.8*)
RPSMP
(17.7)
—
4.425
—
Lactose
(11.9)
—
—
2.965
AMF
6.2
1.55
1.55
1.55
Lecithin
0.57
0.1425
0.1425
0.1425
Vanillin
0.03
0.0075
0.0075
0.0075
TOTAL
100
25.00
25.00
25.00
*Quantity of SMP required in trial 3
[0082] The samples were manufactured according to chocolate manufacturing processes well known to those skilled in the art. The surface colour of the moulded chocolate blocks was measured using a Minolta Chromameter.
[0000]
Colour Measurements
Sample ID
L
a
b
1. Control 100% SMP
43.18
7.02
7.70
2. RPSMP
44.45
7.37
8.25
3. SMP/Lactose Blend
42.99
7.06
7.14
[0083] Slight differences were noted in colour for the SMP/Lactose blend compared with the two other chocolate samples, however this difference was not significant, indicating that milk powder type had little effect on the overall colour readings.
[0084] The particle size of the chocolates was measured using a digital micrometer. The results shown are an average of three consecutive measurements. These measurements only act as a guide and do not give the particle size distribution of the chocolate.
[0000]
Sample ID
Particle Size (μm)*
1. Control 100% SMP
23
2. RPSMP
22
3. SMP/Lactose Blend
20
*average of three consecutive measurements
[0085] All chocolates manufactured had a similar particle size, indicating similar response to processing conditions by all formulations.
[0086] The plastic viscosity is a measure of how easily the chocolate flows once it has started flowing. The yield value is the force required to start the chocolate flowing. The viscosity and yield values given in the table below were measured according to the NCA/CMA Viscosity Method.
[0000]
Plastic Viscosity
Yield Value
Sample ID
(Poise)
(Dynes/cm 2 )
1. Control 100% SMP
21.12
159.06
2. RPSMP
23.21
187.98
3. SMP/Lactose Blend
22.91
194.42
[0087] There was some variation within viscosity results, with both the RPSMP and the SMP/Lactose blend producing chocolate samples that had a slightly higher viscosity compared with the control. The RPSMP milk powder and the SMP/Lactose blend both had a slightly higher yield values compared to the control, which would indicate that more force would be required to get these masses of chocolate moving.
[0088] The “snap” test is a three point bend test which mimics the breaking of a chocolate block into two pieces. This will give comparative measurements as to the hardness of the chocolate, which will give an indication of the chocolate texture and effects of the powders on the chocolate texture. The ‘snap’ value of the chocolates given in the table below were measured using a TA-XT2 texture analyzer.
[0000]
Sample
Snap (grams)*
1. Control 100% SMP
3752
2. RPSMP
4191
3. SMP/Lactose Blend
4893
*average of three consecutive readings
[0089] The SMP/Lactose blend chocolate sample required a greater force to initiate snap compared to the control and RPSMP formulations.
[0090] The hardness measurement of a product is a compression test and closely simulates the human action of taking the initial bite. The hardness of the chocolate samples, as shown in the following table, was measured using a TA-XT2 texture analyzer.
[0000]
Sample
Hardness (grams)*
1. Control 100% SMP
1166
2. RPSMP
1168
3. SMP/Lactose Blend
1225
*average standard deviation (±31 g)
[0091] The SMP/Lactose blend chocolate was found to be slightly harder than the control and the RPSMP samples.
[0092] An informal taste panel was used to assess the flavour of the chocolate samples. The results of these tests are given in the table below.
[0000]
Sample
Description
1. Control 100% SMP
Sweet, clean creamy flavour
with a smooth mouthfeel.
2. RPSMP
Sweeter than control, slight
caramelized flavour, smooth
mouthfeel, creamy
3. SMP/Lactose Blend
Sweet, less overall milk
flavours, less creamy, smooth
mouthfeel
[0093] All the chocolate samples manufactured were found to have an acceptable flavour. Some flavour variations were noted in the SMP/Lactose blend sample, which had relatively less flavour compared to the other samples.
[0094] The main finding of the above study is that chocolate manufactured having 100% of standard SMP replaced by RPSMP manufactured in accordance with the invention is likely to meet normal quality requirements for chocolate.
Example 8
Use of Reduced Protein Full Cream Milk Powder (RPFCMP) in Chocolate
[0095] A trial was done to assess the suitability of RPFCMP in replacing full cream milk powder (FCMP) in a chocolate formulation. Two chocolate samples were prepared and examined, on a control including FCMP and the test batch featuring 100% replacement of FCMP with a RPFCMP prepared in accordance with Example 2. Both of these chocolates manufactured were assessed in terms of ease of processing and handling, colour, Casson plastic viscosity, yield value, particle size, hardness, snap and organoleptic attributes.
[0096] The base milk chocolate formulation for 20 kg batches of the two chocolate formulations is shown the table below.
[0000]
Control FCMP
Full Cream Choc
Ingredient
% by mass
(Kg)
Plus (Kg)
Caster Sugar
43
8.6
8.6
Cocoa Butter
21
4.2
4.2
Cocoa Liquor
11.5
2.3
2.3
Control FCMP
(23.9)
4.78
—
RPFCMP
(23.9)
—
4.78
Lecithin
0.57
0.114
0.114
Vanillin
0.03
0.006
0.006
TOTAL
100
20.00
20.00
[0097] The samples were manufactured according to chocolate manufacturing processes well known to those skilled in the art.
[0098] The surface colour of the moulded chocolate blocks was measured using a Minolta Chromameter. The results are shown in the following table:
[0000]
Colour Measurements
Sample ID
L
a
b
1 . Control FCMP
42.35
7.19
10.03
2. RPFCMP
40.30
6.99
9.13
[0099] Milk powder type was found to have little effect on the overall colour readings. The particle size of the chocolates was measured using a digital micrometer. The results given are an average of three consecutive measurements. These measurements only act as a guide and do not give the particle size distribution of the chocolate.
[0000]
Sample ID
Particle Size (μm)*
1. Control FCMP
19
2. RPFCMP
20
*average of three consecutive measurements
[0100] Both chocolates manufactured had a similar particle size, indicating similar response to processing conditions.
[0101] Plastic viscosity is a measure of how easily the chocolate flows once it has started flowing. The yield value is the force required to start the chocolate flowing. The viscosity and yield value of both formulations were measured according to the NCA/CMA Viscosity Method, and the results are given in the following table.
[0000]
Plastic Viscosity
Yield Value
Sample ID
(Poise)
(Dynes/cm 2 )
1. Control FCMP
29.86
208.43
2. RPFCMP
28.10
230.87
[0102] The “snap” test is a three point bend test which mimics the breaking of a chocolate block into two pieces. This will give comparative measurements as to the hardness of the chocolate, which will give an indication of the chocolate texture and effects of the powders on the chocolate texture. The ‘snap’ values of the chocolates were measured using a TA-XT2 texture analyser, and are shown in the following table.
[0000]
Sample
Snap (grams)
1. Control FCMP
4610
2. RPFCMP
4892
[0103] The RPFCMP product was found to require slightly more force to initiate snap in comparison to the control FCMP product.
[0104] The hardness measurement of a product is a compression test and closely simulates the human action of taking the initial bite. The hardness of the two chocolate formulations was measured using a TA-XT2 texture analyzer. The results are shown in the following table.
[0000]
Sample
Hardness (grams)*
1. Control FCMP
1341
2. RPFCMP
1448
*average standard deviation (±75.6 g)
[0105] An informal taste panel was used to assess the flavour of the chocolate samples. It must be noted that the results are subjective and as a limited number of people were involved in this assessment further investigation would be required to accurately assess consumer preference.
[0000]
Sample
Description
1. Control FCMP
Smooth and creamy
mouthfeel, slightly
caramelized, good
chocolate flavours
2. RPFCMP
Smooth and creamy
mouthfeel, more
caramelized flavours and
slightly sweeter compared
to commercial powder
[0106] Both chocolate samples manufactured were found to have an acceptable flavour, with the RPFCMP product having slightly more caramelized and sweeter flavours than the Control FCMP product.
[0107] The main finding of the above study is that chocolate manufactured having 100% of standard FCMP replaced by RPFCMP manufactured in accordance with the invention is likely to meet normal quality requirements for chocolate.
Example 9
Use of Reduced Protein SMP in Bakery Applications
[0108] Trials have been carried out to determine the suitability of RPSMP prepared in accordance with Example 1 as a replacement for skim milk powder in a range of bakery applications—bread, Asian style Pan Dan cake, biscuits, donuts and custard. The main finding from this study was that the use of both milk powders improved the quality and acceptability of these baked products, and that this effect was enhanced in some applications by the use of the RPSMP as compared with use of SMP.
Example 10
Use of Reduced Protein Full Cream Milk Powder (RPFCMP) in UHT Milk
[0109] An 8.7% protein RPFCMP containing 23.3% milk fat was prepared according to the process described in Example 2. The effectiveness of the milk powder was evaluated by inclusion in UHT milk formulations.
[0110] A control recombined milk was prepared from whole milk powder (WMP) to give a composition including 3.3% fat, 12.5% total solids and 3.35% protein. A stabiliser (Kelcogel HMB) was added at 0.1%.
[0111] The mix was treated in an UHT process at 138° C. for 3 seconds, cooled to 70° C., homogenised at 30 & 20 Bar (in a double stage homogenisation process), and cooled to 30° C. Samples were refrigerated immediately after collection.
[0112] Two further batches were prepared, in which a RPFCMP prepared according to the invention was used to replace WMP solids to give similar composition to the control. WMP solids substitution was made at 50% and 70%. The calculated protein levels were 2.34% and 1.95%. The milks were processed with the same conditions as the control. Each of the samples then underwent informal sensory evaluation.
[0113] Very few discernable differences were found between samples. Almost all tasters had a preference for the 50% replaced product, which was judged to have a slightly sweeter flavour and, surprisingly, a much fresher and ‘less cooked’ flavour.
[0114] There were no differences in the thickness and mouth-feel characteristics of the three milks.
Example 11
Use of Reduced Protein Skim Milk Powder (RPSMP) in Recombined Sweetened Condensed Milk (RSCM)
[0115] Three batches of RSCM were prepared according to the formulations given in the following table. Of the three batches, two represented partial (20% and 50%) replacement of SMP with a reduced protein SMP prepared according to the invention.
[0000]
Property
20% SMP
50% SMP
Ingredient
100% SMP
Replacement
Replacement
Skim Milk Powder
1.59
1.272
0.795
RPSMP
—
0.318
0.795
Palm Oil
0.585
0.585
0.585
Sugar
3.375
3.375
3.375
Water
2.08
2.08
2.08
Total Solids
71.9%
71.9%
71.9%
Viscosity (cP)
2,100
6,100
12,000
[0116] The batches were mixed, heated to 80° C. and vacuum cooled to 40° C. The batches were seeded with lactose at 45° C. Surprisingly, the viscosity of the RSCM increased as the reduced protein SMP content was increased—this was unexpected, given the lower protein content of the reduced protein SMP.
Example 12
Use of Protein Skim Milk Powder (RPSMP) in Ice Cream
[0117] Two batches of ice cream were prepared. The first was prepared as a control using SMP. The second was prepared using a RPSMP, prepared according to the invention, replacing the SMP as the sole source of non-fat milk solids. The ice creams were prepared according to the formulations given in the following table:
[0000]
Ingredients (%)
Control
Test
SMP
12.0
—
RPSMP
—
12.0
Sucrose
14.0
14.0
Vegetable Fat
10.0
10.0
Stabiliser
0.5
0.5
Vanilla Flavour
0.1
0.1
Water
63.4
63.4
[0118] Both ice cream blends were heat treated, homogenised, cooled, crystallised and churned according to a standard ice cream manufacturing process well known to those skilled in the art.
[0119] No differences were noticed between the two batches during processing. Both ice cream products had similar over-run and stability and were judged to be very similar organoleptically.
[0120] All of the above results attest to the ability of waste milk permeate product to be used in the manufacture of a modified milk powder which can partially or wholly replace standard milk powders in various food-related applications. This results in a commercially viable disposal mechanism for said permeates.
[0121] It will be understood by those skilled in the art that the above examples of the inventive method, and uses of the resultant product, represent a relatively limited indication of the ways in which such milk products may be disposed of, whilst remaining within the spirit and scope of the invention.
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A method for the processing of milk ultrafiltration permeate created during the manufacture of milk protein concentrate (MPC) and/or whey protein concentrate (WPC) to produce a reduced-protein milk powder, which nevertheless has useful functional and sensory properties.
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FIELD OF THE INVENTION
The present invention relates generally to hardcopy devices, particularly but not exclusively to inkjet printers and to methods of operating such printers.
BACKGROUND TO THE INVENTION
As is well known in the art, conventional inkjet printers generally employ one or more inkjet cartridges, often called “pens”, which eject drops of ink onto a page or sheet of print media. The pens are usually mounted on a carriage, which is arranged to scan relative to a sheet of print media as the pens print a series of individual drops of ink on the print media. Often, the pens scan across a scan axis relative to a stationary sheet of print media. The series of drops collectively form a band or “swath” of an image, such as a picture, chart or text. Between scans, the print medium is advanced relative to the scan axis. In this manner, an image may be incrementally printed. In other arrangements, the pens, in the form of a page wide array for example, may remain stationary with the print media being past the print bar.
The distance which an ink drop travels from a print head to the ink receiving surface of the print medium is often known as the pen-to-paper spacing. For high-quality image formation the pen-to-paper spacing is desirably precisely controlled. If the spacing to too little, the risk that a print head may impact against the print media increases. This is especially likely where the print media expands on absorbing water contained in the ink printed on its surface. This expansion may cause undulations or wrinkles in the plane of the print media. As a consequence, the distance between the print media and the print head decreases at some localized points. If, on the other hand, the pen-to-paper spacing is too great, the ejected dots may not be accurately positioned on the surface of the print medium. Other artefacts which also degrade print quality may also occur.
The pen-to-paper spacing in an inkjet printer is set during assembly of the printer. This process is generally repeated only when the carriage is replaced in a major servicing operation.
SUMMARY OF THE INVENTION
According to one aspect of the invention, there is provided a printer device comprising a mechanism adapted to generate an image on an image surface, the device comprising a sensor adapted to image a predetermined optical object located substantially on the image surface, the device being adapted to determine at least one dimension of the object's image and thereby determine the distance separating the mechanism and the image surface.
In certain embodiments of the present invention, the distance separating the image forming mechanism and a surface upon which an image may be formed may be readily determined, without the need for a time-consuming servicing operation. In certain embodiments of the present invention, the process determining the separation distance, or pen-to-paper spacing, may be performed in a manner which is transparent to the user.
In certain embodiments of the invention, a printer or hardcopy device may readily verify that that the separation distance lies within acceptable tolerances. In this manner, the likelihood of subsequent print defects and other incorrect operation may be significantly reduced. In some embodiments, the printer or hardcopy device is adapted to verify that the pen-to-paper spacing is satisfactory whenever new print media is loaded. In this manner, a user may not be required to input the paper thickness into the printer. This may be used to obviate the risk of an incorrect entry.
In some embodiments of the invention, the printer is adapted to allow the separation distance, or pen-to-paper spacing, to be subsequently adjusted if required, in order to bring it within predetermined values. This adjustment may be implemented either manually or automatically.
The present invention also extends to the corresponding methods. Furthermore, the present invention also extends to computer programs, arranged to implement the methods of the present invention. Further aspects of the invention will be apparent from the following description and appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
For a better understanding of the invention and to show how the same may be carried into effect, there will now be described by way of example only, preferred embodiments, methods and processes according to the present invention with reference to the accompanying drawings in which:
FIG. 1 is a schematic, perspective view of an image-forming device, according to an embodiment of the invention;
FIG. 2 a is a schematic, perspective view of a media-positioning sensor, according to an embodiment of the invention;
FIG. 2 b is a schematic representation of the optical characteristics of the media-positioning sensor of FIG. 2 a;
FIG. 3 is a block diagram of an image-forming device, according to an embodiment of the invention;
FIG. 4 is a flowchart of a method, according to an embodiment of the invention;
FIG. 5 a is a schematic illustration of an object which may be imaged according to an embodiment of the invention;
FIGS. 5 b - d are diagrams illustrating exemplary images of the object of FIG. 5 a generated by a media-positioning sensor according to an embodiment of the invention.
DETAILED DESCRIPTION OF THE INVENTION
In the following detailed description of exemplary embodiments of the invention, reference is made to the accompanying drawings that form a part hereof, and in which is shown by way of illustration specific exemplary embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention. Other embodiments may be utilized, and logical, mechanical, and other changes may be made without departing from the spirit or scope of the present invention. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the present invention is defined only by the appended claims.
FIG. 1 shows a perspective view of an image-forming device, according to an embodiment of the invention. The device includes a shaft 112 on which a mechanism, or scanning carriage, 114 is slidably situated. The mechanism 114 has a left side 124 , a right side 126 , a front 122 , and a bottom 120 . The mechanism supports one or more printing heads (illustrated in FIG. 2 b ); in the present embodiment these are conventional inkjet print heads. The mechanism 114 is able to move back and forth along a scanning axis 106 , as indicated by the bi-directional arrow 108 . As the mechanism moves back and forth, the print heads may be controlled to eject ink on print media 102 located beneath the mechanism 114 .
As can be seen from the figure, a sheet of print media 102 is supported by a print platen 128 in the region where the media receives ink from the print heads. The media 102 is advanced by a roller 118 , which rotates in the direction indicated by the arrow 116 . This causes the media 102 to move along a media axis 104 that is perpendicular to the scanning axis 106 , as indicated by the arrow 110 . Also illustrated in the figure is the axis 105 , which lies perpendicular to both the media and scanning axes. In this embodiment, the axis 105 may be thought of as the vertical axis of the image-forming device.
The mechanism 114 also supports a media sensor 132 according to the present embodiment. The media sensor 132 is located in the lower surface 120 of the mechanism 114 ; consequently, the sensor 132 is not seen in FIG. 1 , but is illustrated schematically in FIGS. 2 a and 2 b . The sensor is located such that it may sense or image the upper surface of the media 102 , either as the mechanism 114 is scanning across the scan axis 106 or whilst the mechanism 114 is stationary.
FIG. 2 a shows the media-positioning sensor 132 in more detail, according to an embodiment of the invention. The sensor 132 includes an optical sensing mechanism 304 , an illumination mechanism 306 , such as a light-emitting diode (LED), and a controller 302 . The illuminating mechanism 306 illuminates a portion 310 of the media 102 , as is indicated by the rays 308 , so that the optical sensing mechanism 304 is able to capture a satisfactory image. For the sake of clarity, the platen 128 is not illustrated in this figure. The optical sensing mechanism 304 captures an image of a portion 310 of the media 102 that lies beneath the mechanism 304 , as indicated by the arrow 312 .
FIG. 2 b schematically illustrates the pen-to-paper spacing “d” between a pen 314 and the upper, planar surface of a sheet of print media. In the figure three different exemplary pen-to-paper spacings d 1 , d 2 and d 3 are illustrated. The distances d 1-3 in this example are measured along the vertical axis 105 of the image forming mechanism between the nozzle plate, or ink ejecting surface of the pen and the ink receiving or upper surface of the print media. At the distance d 1 , the ink receiving surface of the print media is labelled P 1 . At the increased distance d 2 , the ink receiving surface of the print media is labelled P 2 and at the further increased distance d 3 , the ink receiving surface of the print media is labelled P 3 . The variation in the distances d 1-3 may in practice be caused by the use of print media of varying thicknesses. Alternatively, the bushes supporting the scanning carriage and pens may wear with use, thus progressively reducing the pen-to-paper spacing for media of a given thickness.
Also shown in the figure is a schematic of the optical sensing mechanism 304 illustrating the optical characteristics of the optical sensing mechanism 304 . As can be seen from the figure, the optical sensing mechanism 304 has a sensor element 304 a , which may be a charge-coupled device (CCD) sensor, a complementary metal-oxide semiconductor (CMOS) sensor, or another type of suitable optical sensor. The optical sensing mechanism 304 also has a conventional non-telecentric optical train 304 b for generating an image of an object on the sensor element 304 a . In the figure, the optical train 304 b is illustrated schematically as a single optical element. However in practice a number of optical elements may be used.
In the present example, the optical sensing mechanism 304 is in a known, fixed position in the vertical axis 105 in relation to the print head 314 . In this example, this “offset” distance is labelled “x” and represents the distance between the ink ejecting surface of the print head 314 and the surface of the sensor on which the an image is formed. Thus, each of the ink receiving surfaces of the print media, or planes P 1-3 forms an object plane a different distance from the optical sensing mechanism 304 .
As can be seen from the figure, an object in the form of an arrow is schematically illustrated on each of the three object planes P 1-3 . The objects on planes P 1-3 are respectively labelled O 1-3 . In this example, each of the objects O 1-3 has the same dimensions and the same relative position on its respective plane as the other two objects.
Due to the optical characteristics of the non-telecentric optical train, the dimensions of the images of the objects O 1 , O 2 and O 3 formed on the sensor varies with the distance separating each of the objects from the optical sensing mechanism 304 and/or the sensor element 304 a . That is to say that generally as the distance separating an object from the optical sensing mechanism 304 decreases, the dimensions of its image on the sensor increase; i.e. it is magnified to a greater extent. Conversely, as the distance separating an object from the optical sensing mechanism 304 increases, the dimensions of its image on the sensor generally decrease.
For each of the objects O 1-3 , the chief ray through the optical sensing mechanism 304 is illustrated in the figure. For the sake of clarity, the images are not illustrated in the figure. However, in each case, the length of the image of each object O 1-3 is illustrated by arrows, labelled L 1-3 , respectively. As can be seen, the object O 1 lies closest to the optical sensing mechanism 304 and its image is the most highly magnified, having a dimension of L 1 , measured from the optical axis of the system “y”. The object O 3 lies furthest from the optical sensing mechanism 304 and its image is the least magnified, having a dimension of L 3 . The object O 2 lies an intermediate distance from the optical sensing mechanism 304 and its image is correspondingly magnified to an intermediate degree, having a dimension of L 2 .
In this manner, it will be understood that a set of relationships (this may be in the form of a look up table or one or more mathematical functions) may be determined, for a given operational set up and known size of object, relating a measured dimension of the image of that object to the distance between the optical sensing mechanism 304 and the object. By using, for example, a mark or test pattern of known dimensions on the surface of a sheet of print media as the object, the distance separating the mark, and therefore the ink receiving surface of the print media, from the optical sensing mechanism 304 may be determined. Furthermore, since the positional relationship between the optical sensing mechanism 304 and the print head is known (this may be a constant offset distance, for example) the pen-to-paper spacing may readily be derived.
Referring back to FIG. 2 a , the controller 302 , which is more generally a controlling mechanism, may be software, hardware, or a combination of software and hardware. The controller 302 controls the mechanisms 304 and 306 so that images are captured and media portions are illuminated at desired times. The images captured may be of marks of known dimensions printed on the surface of the print media by the printhead 314 , for example.
One example of a media-positioning sensor suitable for use in embodiments of the present invention is described in U.S. Pat. No. 6,118,132 by Barclay, J. Tullis entitled, “System for Measuring the Velocity, Displacement and Strain on a Moving Surface or Web of Material” assigned to the assignee of the present invention and is herein incorporated by reference in its entirety.
FIG. 3 shows a block diagram representation of an image-forming device 400 , according to an embodiment of the invention. As can be appreciated by those of ordinary skill within the art, the image-forming device 400 may include components in addition to and/or in lieu of those depicted in FIG. 3 . The image-forming device 400 may be a fluid-ejection device. The image-forming device 400 specifically is depicted in FIG. 3 as including a fluid-ejection mechanism 402 , a media-advance mechanism 404 , a carriage-advance mechanism 406 , a media-positioning sensor 408 , a controller 410 and a look up table 412 . It will be understood that in general the various elements in FIG. 3 correspond to the elements described with reference to FIGS. 1 and 2 . For example, the fluid-ejection mechanism 402 may comprise one or more inkjet print heads, such as that illustrated in FIG. 2 b . Furthermore, the media-positioning sensor 408 may correspond to the optical sensing mechanism 304 illustrated in FIG. 2 a , possibly including the illumination mechanism 306 . The controller 410 illustrated in FIG. 3 may correspond to the controller 302 , illustrated in FIG. 2 a . In some embodiments, the controller 410 may control the operation of the media-positioning sensor 408 and also the operation of the image-forming device 400 in general. In other embodiments, separate controllers may be employed for these functions. The look up table 412 may be conventionally stored in memory associated with the controller 410 .
FIG. 4 illustrates a method 500 , according to an embodiment of the invention. The method 500 will now be described with reference to the image-forming devices of FIG. 1-3 .
At step 502 of the method, the controller 410 initiates a pen-to-paper measurement routine. This may be implemented periodically, or in response to particular events. Such events may include, for example, the loading of new print media into the image-forming device or an operator input.
At step 504 the controller 410 controls the fluid ejection mechanism 402 , together with the media and carriage advance mechanisms 404 , 406 to print a predetermined test pattern on a sheet of print media in a desired location. This may be performed in a conventional manner. In the present example, the test pattern consists of two circles 600 a , 600 b (illustrated in FIG. 5 a ) of known diameter, separated from one another by a known distance “a”.
At step 506 , the controller 410 controls the media-positioning sensor 408 to image the pattern, which may be viewed as the optical object, printed at step 502 . The media-positioning sensor 408 may be stationary whilst it images the pattern. Alternatively, the media-positioning sensor 408 may image the pattern whilst the carriage traverses the scan axis. This may be, for example, immediately after the pattern is printed. It will thus be understood that the optical object may be moving relative to the media-positioning sensor 408 during the imaging step 506 . Examples of images of the object are shown in FIGS. 5 b - d.
At step 508 , the controller 410 analyses the image of the object. In this step of analysis, the controller 410 measures a predetermined dimension of the image. In the present example, the dimension measured is the distance “a” separating the centres of the two circles 600 a , 600 b in the image. It will however be appreciated that any convenient dimension or combination of dimensions may instead be measured. This may be achieved using any conventional techniques, such as that described in U.S. Pat. No. 6,118,132.
The process of analysing the image of the object is graphically illustrated in FIGS. 5 b - d . FIGS. 5 b - d illustrate exemplary images generated by the media positioning sensor 408 , which are not to scale, of the printed test pattern shown in FIG. 5 a . As can be readily seen from the figures, each of FIGS. 5 b - d , shows an image of the test pattern made up of circles 600 a , 600 b . In the images 5 b - d , the circles 600 a , 600 b are referenced: 600 a ′, 600 b ′; 600 a ″, 600 b ″; and, 600 a ′″, 600 b ′″, respectively. Each of the figures shows the image magnified to a different extent. As has been described with reference to FIG. 2 b , the difference in magnification of the images shown in FIGS. 5 b - d is caused by different distances between the media positioning sensor 408 and the optical object when the different images were captured; i.e. varying pen-to-paper spacing. As can be seen from FIGS. 5 b - d , the image shown in FIG. 5 b is magnified to a greater extent that is the image shown in FIG. 5 c . Similarly, the image shown in FIG. 5 c is magnified to a greater extent than is the image shown in FIG. 5 d . Thus, the image at high magnification illustrated in FIG. 5 b may correspond to a relatively small distance between the media positioning sensor 408 and the surface of the print medium, as is represented by the position P 1 of the print medium FIG. 2 b . The image at low magnification illustrated in FIG. 5 d may correspond to a relatively large distance between the media positioning sensor 408 and the surface of the print medium, as is represented by the position P 3 of the print medium FIG. 2 b . The image at an intermediate magnification illustrated in FIG. 5 c may correspond to an intermediate distance between the media positioning sensor 408 and the surface of the print medium, as is represented by the position P 2 of the print medium FIG. 2 b.
The distance “a” separating the centre of imaged circles 600 a , 600 b in FIGS. 5 b - d are referenced a′, a″ and a′″, respectively. As can be seen from the figures, this distance varies with the degree of magnification of the image; and so with the pen-to-paper spacing. Thus, this distance a′ in FIG. 5 b is greater than the equivalent distance a″ in FIG. 5 c . Similarly, the distance a″ in FIG. 5 c is greater than the equivalent distance a′″ in FIG. 5 d.
At step 510 , the controller 410 finds in the look up table 412 a measured dimension corresponding to that distance “a” measured at step 508 . Associated with the measured dimension value in the look up table 412 is a value for the distance separating the nozzle plates of the pens and the ink receiving surface of the print media; i.e. the pen-to-paper spacing. This look up table 412 may generated and loaded into memory associated with the image forming device on manufacture using conventional techniques. The skilled reader will understand that not all values for the measured dimension and the corresponding pen-to-paper spacing need be stored in the look up table 412 . Intermediate values may be determined by the controller 410 using a conventional interpolation process.
At step 512 , the controller 410 determines whether the pen-to-paper spacing value obtained at step 510 lies within the range of values permitted. If, for example, the bushings of the scan axis have become too worn, or if the user has inserted print media that is too thick to allow reliable printing, then the controller may generate a warning message and may prevent printing from occurring at step 514 . If on the other hand, the controller determines that the pen-to-paper spacing value obtained at step 508 lies within the range of values permitted, then the method may proceed to step 516 .
At step 516 , the controller may determine whether the operation of the image-forming device should be modified in dependence upon the measured pen-to-paper spacing.
As the skilled reader will appreciate, in scanning printers which have pens which are offset from one another in the scanning direction, nozzles in different pens must fire at different times in order to print dots at the same point along the scan axis. This firing delay between pens depends upon the spacing between the pens in the scan axis direction and the scan speed, together with the directionality of ink drop ejection in the scan direction of the print heads in question. Generally, it is an aim of pen manufacture that each pen ejects ink at the same angle. However, due to manufacturing variations, this ink drop ejection angle may vary significantly between pens. Because of this, when pens are changed, test patterns are conventionally printed so that the ink drop ejection angle characteristics of the pens can be measured. The appropriate delays between the firing of one pen and another are then calculated to ensure that ink drops ejected by those pens that are meant to be located on the print media at the same point along the scan axis, are so located. However, these delays are dependent upon the pen-to-paper spacing. Therefore, if the pen-to-paper spacing subsequently changes, pens with different ink drop ejection angle characteristics will print drops, which should occupy the same position on the media in the scan axis direction, at different positions on the media in the scan axis direction. This may be viewed as giving rise to a “registration” type error.
Thus, at step 516 , the controller may determine the delay required between the firing of one pen and another, in dependence upon the measured pen-to-paper spacing, in order to reduce this registration type error. The required delays may be determined in any suitable manner; for example through the use of further look-up-tables. The controller may then modify the printing control algorithms to incorporate the required delays.
At step 516 , the controller ends the method 500 . The image-forming device may then be ready to commence printing a print job.
FURTHER EMBODIMENTS
In the above description numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent however, to one skilled in the art, that the present invention may be practiced without limitation to these specific details. In other instances, well known methods and structures have not been described in detail so as not to unnecessarily obscure the present invention.
For example, the skilled reader will appreciate that although the above embodiment was described with reference to a scanning inkjet printer, it may also be applied to a non-scanning printer, such as a page wide array. Furthermore, the present invention may also be applied to any image forming device where it is desirable to measure or control the distance between a printing mechanism and image receiving surface. Thus, embodiments of the present invention may be applied to laser printers and liquid electrophotographic printers amongst others, for example.
In the above embodiments it has been assumed that the pen-to-paper spacing is constant across the length of the scan axis. In practice, in certain printers, this may not be the case. This may be due to various factors, such as: a lack of manufacturing precision; incorrect set up; or, uneven wear over time. Where the pen-to-paper spacing is not constant across the length of the scan axis, the firing delay between different pens separated in the scanning direction is preferably varied across the scan axis in accordance with the local value of the pen-to-paper spacing. That is to say that the firing delay between such pens preferably varies in dependence upon the position of those pens, or the carriage in which they are mounted, across the scan axis. In this way, ink dots printed by different print heads may be correctly registered along the length of the scan axis. In one embodiment of the invention, the pen-to-paper spacing may be measured, as described above, at various points across the scan axis. In this manner, a pen-to-paper spacing profile may be generated for up to the entire scan axis length. The skilled reader will appreciate that the number of pen-to-paper spacing measurements could be any reasonable number. Interpolation techniques could be used to estimate the pen-to-paper spacing in areas where no measurement is made, should this be required.
The skilled reader will appreciate that such a profile could be used in a variety of printing systems other that that described; for example, a printing system in which the image is generated on directly on a drum, or in which print media is supported on a drum platen. Furthermore, where a drum platen is employed, such a profile could be additionally or alternatively be generated for the pen-to-paper spacing in a circumferential direction around the perimeter of the drum. In this manner, an eccentricity in the drum mounting, which causes a varying pen to paper spacing as the drum rotates relative a printhead could be compensated for. One or more such circumferential profiles could in practice be generated at corresponding locations along the rotational axis of the drum.
The skilled reader will also appreciate that such profiles may be generated or verified periodically, for example as part of a user instigated servicing routine. Alternatively, it could be generated or verified on an almost continuous basis. For example, where a printer is printing text of given characteristics (font style and size etc.) the media-positioning sensor may continually image given letters, for example, under the control of the controller. In this manner, the controller may employ the techniques descried above to determine the local pen-to-paper spacing at many point across the scan axis and/or circumferentially about a rotating platen if appropriate, in an ongoing manner during normal use. In this way, time, print media and ink need not be expended in order to implement the pen-to-paper spacing measurement process of embodiments of the present invention.
Furthermore, in embodiments of the invention, a printer may be provided with a scan axis assembly that can be moved relative (towards or away) to the platen. In this manner, the pen-to-paper spacing may be modified in accordance with the determined pen-to-paper spacing measurement. For example, if a user inserts a sheet of print media which reduces the pen-to-paper spacing to an undesirably low level, the pen-to-paper spacing may then be increased to a normal level. This may be achieved manually. In this case, the user may make a suitable mechanical adjustment to the pen-to-paper spacing (using for example a cam system or a differential screw system). In such a situation, the user may follow instruction ouput by the printer on a user readable display, for example. Alternatively, the printer may be provided with one or more motors with which the pen-to-paper spacing may be adjusted automatically.
In the above-described embodiments, the media-positioning sensor was located on the scanning mechanism or carriage. However, the skilled reader will understand that in practice, it may be located in any convenient location. Thus, it may be located statically in relation to the platen. In any event, however, it is preferable that it does not undesirably obstruct moving elements of the printer, such as the advance of the carriage or the media.
In the above-described embodiments, the optical object imaged by the media-positioning sensor was printed by the printer. However, the skilled reader will understand that in practise, any suitable object may be used. For example, suitable inherent physical aspects of the media may be used as optical objects. These may be watermarks or elements or particles embedded in the media. Such elements or particles may take the form of metal foils, for example, as used in security papers.
It will also be understood that in simple embodiments of the invention, a printer may be adapted to compare a measured dimension or area of an image with a single stored comparison value. This may allow the printer to determine whether the pen-to-paper spacing lies above or below a given minimum threshold. In dependence upon this determination, printing may be permitted or inhibited.
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A printer device comprising a mechanism adapted to generate an image on an image surface, the device comprising a sensor adapted to image a predetermined optical object located substantially on the image surface, the device being adapted to determine at least one dimension of the object's image and thereby determine the distance separating the mechanism and the image surface.
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CROSS-REFERENCE TO RELATED APPLICATIONS
Copending application U.S. Ser. No. 507,775, filed September 20, 1974, now U.S. Pat. No. 3,997,416, assigned to the assignee of the present application, discloses a method and apparatus for analyzing gaseous mixtures including measurement of small concentrations of vinyl chloride.
BACKGROUND OF THE INVENTION
Concern with the health hazards associated with industrial exposure to materials, in particular vinyl chloride, has caused the allowable concentration of vinyl chloride to be reduced substantially from the previous standards to levels in air of one part vinyl chloride to every million parts of air, averaged over an eight-hour period. Levels of vinyl chloride in the atmosphere may exceed one part per million for short periods; however, it must average no more than five parts per million for any fifteen minute period over an eight-hour span.
Various methods for reducing vinyl chloride emissions from PVC manufacturing and fabrication plants have been proposed. These include the adsorption of the vinyl chloride monomer from vent gases on activated charcoal with the monomer regenerated with steam and the vinyl chloride re-introduced into the process. Other control techniques include thermal decomposition of the monomer or solvent scrubbing.
SUMMARY OF THE INVENTION
The invention relates to a method and system for controlling gaseous emissions, and particularly vinyl chloride, by exposing such emissions to ultraviolet light of sufficient intensity to decompose certain components of interest into other materials and, thereafter, absorbing such decomposition products in a scrubber which substantially eliminates the vinyl chloride and most other decomposition products from being exhausted to the atmosphere.
As specifically applied to the control of plant emissions from processes and stacks, the emissions are passed through a chamber where it is exposed to ultraviolet light of adequate intensity so as to decompose essentially all of the vinyl chloride present. The resulting decomposition products consist primarily of hydrogen chloride with trace amounts of phosgene and chlorine. Thereafter, the decomposed products are passed through apparatus such as a water scrubber, which absorbs the products of decomposition, thereby eliminating them from subsequently being released to the atmosphere.
The invention also may be applied to a number of other compounds, e.g. nitric oxide, hydrogen sulfide, and carbon disulfide, which are contained in gaseous emissions. The compounds are limited only by their tendency to decompose when exposed to ultraviolet light and on the ability to remove them in apparatus, subsequent to exposure to the ultraviolet and prior to exhaust to the atmosphere.
BRIEF DESCRIPTION OF THE DRAWINGS
The single FIGURE is a schematic diagram illustrating the invention in a typical exhaust system for plant emission control.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Although the invention relates in a preferred embodiment to the control of vinyl chloride in plant emissions, it also is applicable to other potentially hazardous materials which are desired to be prevented from exhaust to the atmosphere. The description which follows, however, will be primarily directed to the control of vinyl chloride.
Oftentimes, as in polyvinyl chloride manufacturing operations and other plant processes such as PVC fabrication, vinyl chloride will be a principal compound contained in the emissions to the atmosphere. As illustrated in the single FIGURE, there is shown a typical exhaust stack 10 which emits a gaseous mixture from a plant process operation. The mixture is coupled through a conduit 12 connected at an end to the emission stack and at its opposite end to a plenum chamber 14. The chamber 14 preferably is made of stainless steel, although other materials such as fiberglass or carbon steel also can be used, as long as it is substantially corrosion-resistant. A bank of ultraviolet lights 16 and 18 are situated about or on opposite sides of the chamber, such that the gaseous mixture flows through the ultraviolet lights, which emit an intense ultraviolet radiation of sufficient intensity to convert essentially all of the vinyl chloride to decomposition products which include hydrogen chloride and traces of phosgene. A range of ultraviolet radiation intensity typically may be 3 to 6 watts/liter of plenum volume with a preferred range being 3 to 5 watts/liter, and most preferably 4 watts/liter. Suitable ultraviolet radiation may be provided by lamps which emit ultraviolet light. The volume of the chamber is such that the residence time of the exhaust stream in the chamber is about thirty seconds, although the residence period can vary from 20 to 50 seconds depending on the intensity of the ultraviolet light. The criteria for selecting the residence time for a particular operation is based on effective decomposition of containment. The exposure to the ultraviolet radiation will also decompose other components typically contained in plant emission, such as carbon disulfide, hydrogen sulfide, nitric oxide, and other airborne contaminants which can be decomposed by exposure to intense ultraviolet radiation. For example, nitric oxide may be oxidized to nitrogen dioxide by exposure to ultraviolet radiation, which then is absorbed in the scrubber. In another example hydrogen sulfide can be decomposed to sulfur dioxide which can be absorbed in the scrubber.
A conduit 20 is connected at one end to the outlet of the decomposition chamber 14 which contains the ultraviolet lights and at its opposite end to apparatus schematically shown at 22 which in the preferred embodiment comprises a water scrubber. The water may be deionized for best effectiveness or regular tap water also will sulfide. The scrubber per se may be of the conventional type, e.g. venturi type. Alternatively, it may be of the spray chamber type. The gaseous stream containing the decomposition products is transferred via conduit 20 into the scrubber 22 where the decomposition products, particularly the hydrogen chloride, are absorbed. Almost ninety percent decomposition of the vinyl chloride has been obtained in the laboratory, with vinyl chloride concentrations in the input gaseous stream of from 0.1 to 25 parts per million.
The resultant gaseous stream after passing through the scrubber 22 then is exhausted to the atmosphere by means of an exhaust conduit 24. This exhaust will be substantially free of vinyl chloride or at the very least will have reduced the vinyl chloride concentration to an acceptable level. This level can be monitored by sampling the exhaust flowing through conduit 24 by use of the invention of the aforementioned U.S. Pat. No. 3,997,416, by means of extracting a sample via tube 26 and analyzing it as schematically shown at 28. If the measured level of vinyl chloride concentration exceeds a predetermined level, the exhaust can be recycled through a feedback conduit 30 for repassage through the ultraviolet light plenum 14. The recycled exhaust can be fed back directly into the ultraviolet light plenum as shown for recycling with the flow from conduit 12. Also, an automatically controlled valve (normally closed) 32 responsive to the measured level of exhaust can be opened if the level exceeds the predetermined value to permit recycling of the exhaust in response to an appropriate signal (e.g. electrical) provided via connection 34 from the analyzer 28 to the valve 32. The valve, which is per se conventional, would remain closed at levels below the predetermined reference level. Other alternatives may include use of a signal from the stack monitoring sensor 28 to actuate a mechanical blower (not shown) to supply air to the stack to reduce the level of vinyl chloride in the exhaust air to an acceptable level.
While a preferred embodiment and various modifications thereof have been disclosed, it will be apparent to those of ordinary skill in the art upon reading this disclosure, that other modifications and variations can be made. Accordingly, reference should be made to the appended claims for determining the full and complete scope of the present invention.
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A method and system for controlling plant and other gaseous emissions from processes and stacks by decomposing predetermined components, particularly vinyl chloride, of these emissions by exposure to ultraviolet radiation to form less hazardous materials which then are absorbed in a scrubber. This results in the substantial elimination of vinyl chloride and most of the other decomposition products from being ejected into the atmosphere.
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[0001] This application claim priority from co-pending U.S. patent application Ser. No. 13/335,919 filed Dec. 22, 2011 for Systems and Methods for Monitoring and Processing Biometric Data, which application is incorporated herein in its entirety by this reference. The '919 claims the benefit of U.S. Provisional Application No. 61/428,845, filed Dec. 30, 2010 for Systems and Methods for Monitoring and Processing Biometric Data, which application is incorporated herein in its entirety by this reference. This application claims the benefit of the '845 application through the '919 application.
BACKGROUND
[0002] The present invention relates to systems and methods for monitoring a variety of biometric data and environmental data primarily via a dental appliance worn by a human user.
[0003] U.S. Pat. No. 7,481,773 discloses a body temperature monitoring system which includes a mouth guard, a temperature-sensing unit associated with the mouth guard, and an indicator unit responsive to the temperature sensing unit. The indicator unit indicates if a body temperature sensed by the temperature-sensing unit is outside of a pre-selected range. The indicator unit may be programmed to actuate an indicator when the temperature-sensing unit senses one or more temperatures that fall outside the pre-selected range. In one implementation, the indicator unit receives a string of multiple temperature readings and determines which temperatures are valid and invalid, and averages the valid temperatures. A method of monitoring a person's body temperature that parallels the above device is also disclosed. The '773 patent also discloses numerous ways to monitor temperature data to users of the device through mechanical (wireless or wired), audio, visual, and physical means.
[0004] It is therefore apparent that an urgent need exists for an improved real-time monitoring system capable of monitoring a variety of biometric data of one or more users and environmental in their respective environments. This improved monitoring system increases individual safety and performance before, during, and after the monitored session.
[0005] The monitoring system is embodied in an oral appliance that can be made with one or more materials, and be placed in an individual's mouth in a variety of positions, locations, and form factors.
SUMMARY
[0006] To achieve the foregoing and in accordance with the present invention, systems and methods for monitoring biometric and environmental parameters are provided.
[0007] For example, these monitoring systems and methods enable an individual user and/or an observer, such as a coach, trainer, supervisor, or guardian, to closely monitor one or more users in real time or post event. The objective of the monitoring is to enhance individuals' safety and performance in a variety of situations including in athletics, workplace, home, military, firefighting, and recreation.
[0008] In one embodiment, the computerized user monitoring system includes a dental appliance configured to fit substantially inside a mouth of a user. The dental appliance includes one or more temperature sensors. The dental appliance may include one or more additional sensors, such as force, pressure, and/or biometric sensors. The dental appliance also includes a processor coupled to the temperature sensors and any other sensors. The monitoring system may also include one or more display technologies including visual, tactile, and/or audible indicators coupled to the processor.
[0009] In some embodiments, the user monitoring system includes a transmitter for sending data to an external monitoring system worn by the user, so that the user can track their own health and/or performance and be alerted under a wide variety of conditions in real-time, thereby enabling the individual to take any appropriate action. This external user monitoring system includes data storage capabilities that enable the user to review, process, and conduct analyses of their data including milestones, trends, and physiological events to further enhance their well-being, performance and fitness.
[0010] In some embodiments, the user monitoring system includes a transmitter for sending data to an external observer monitoring system, so that the observer can track the health and/or performance of one or more users and be alerted under a wide variety of conditions in real-time, enabling the observer to take any appropriate action. This external observer monitoring system includes a data storage capability that allows the observer to review and to further assess the users' data for future review, processing, analysis and trends.
[0011] In some embodiments, the user monitoring system includes a transceiver for sending information to the observer monitoring system and/or sending information from the observer monitoring system to the user monitoring system.
[0012] In some embodiments, the user monitoring system includes chambers for capturing fluids such as saliva and/or air samples in the dental appliance. In some cases, the additional materials may be added to the oral appliance to facilitate the collection and storage of the fluid and air samples. The collected samples may be analyzed locally in the dental appliances and/or remotely in a laboratory.
[0013] In some embodiments, the user monitoring system includes sensors that measure the amount of certain compounds including oxygen, carbon dioxide, and/or the presence of alcohol.
[0014] Note that the various features of the present invention described above may be practiced alone or in combination. These and other features of the present invention will be described in more detail below in the detailed description of the invention and in conjunction with the following figures.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] In order that the present invention may be more clearly ascertained, some embodiments will now be described, by way of example, with reference to the accompanying drawings, in which:
[0016] FIG. 1 shows a perspective view illustrating one embodiment of the user monitoring system, in accordance with the present invention;
[0017] FIG. 2 shows an exploded view illustrating the components of the embodiment of FIG. 1 ;
[0018] FIG. 3 includes top, front, and side views of the embodiment of FIG. 1 ;
[0019] FIG. 4 shows an exploded view of another embodiment of the user monitoring system illustrating the components of the system of this embodiment in accordance with the present invention;
[0020] FIG. 5 is a perspective view of another embodiment of the user monitoring system in accordance with the present invention;
[0021] FIG. 6 shows an exploded view of another embodiment of the user monitoring system illustrating the components of the system of this embodiment in accordance with the present invention;
[0022] FIG. 7 is a diagram illustrating the customizable functions of the processing circuit in accordance with the present invention;
[0023] FIG. 8 illustrates the user monitoring system and observer monitoring system collecting and sharing biometric and environmental data via a two-way means of communication;
[0024] FIG. 9 illustrates the user monitoring system case in accordance with the present invention which improves form and fit for the user while helping to ensure ease of use in forming and storage;
[0025] FIG. 10 illustrates a summary of the present invention with the embodiment applicable to an athlete and related observer;
[0026] FIG. 11 illustrates the user monitoring system inductive charge case in accordance with the present invention. This is an inductively charged monitoring system;
[0027] FIG. 12 illustrates using kinetic energy from biting down on the appliance to generate electrical power for the appliance;
[0028] FIG. 13 shows another embodiment of the user monitoring system illustrating pulse oximeter technology in accordance with the present invention; and
[0029] FIG. 14 shows another embodiment of the user monitoring system illustrating capnograph technology in accordance with the present invention.
DETAILED DESCRIPTION
[0030] The present invention will now be described in detail with reference to several embodiments thereof as illustrated in the accompanying drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the present invention. It will be apparent, however, to one skilled in the art, that embodiments may be practiced without some or all of these specific details. In other instances, well known process steps and/or structures have not been described in detail in order to not unnecessarily obscure the present invention. The features and advantages of embodiments may be better understood with reference to the drawings and discussions that follow.
[0031] The present invention relates to systems and methods for monitoring a variety of biometric and environmental data related to one or more users at a variety of venues, such as workplaces and sporting or recreational facilities, enabling the user and/or one or more human observers, such as coaches, trainers, parents or supervisors, to monitor the health and performance of these users. To facilitate discussion, FIG. 1 is a perspective, showing one embodiment of the computerized monitoring system 100 in accordance to the present invention. FIG. 2 shows an exploded view illustrating the components of the embodiment of FIG. 1 . FIG. 3 shows the top, front, and side views of the embodiment of FIG. 1 .
[0032] Referring also to FIG. 8 which illustrates an exemplary implementation 800 in accordance with an embodiment of the present invention, one or more (user) monitoring systems 811 , 812 . . . 819 communicate with at least one (external) observer monitoring system, e.g. implemented into a smart phone 820 , which in turn may be communicating with an optional storage system 840 via a computerized network 830 , e.g., the Internet. Monitoring system 100 includes a dental appliance 110 with a recessed compartment 111 for housing a processor 140 which is shielded by a protective cover 180 . The back-end repository not only houses and stores data, it also provides the vehicle and foundation for multiple analytics including, but not limited to, normative data, capturing individual data and tracking changes over time based on captured data from the monitoring system and combining that with other data like weather conditions and time of day. Data is aggregated over individual profiles based on body types, physical activities, and position of the individuals which can be combined with other individual's profiles to create a team profile or group profile of like individuals. Examples of dental appliance 110 include mouth guards, mouth pieces, dentures, dental flippers, braces, retainers, first responder breathing mouth pieces, ventilator mouth pieces, anti-snoring and teeth grinding mouth pieces, infant pacifier, and scuba or snorkeling mouth pieces. Accordingly, many variations (not all shown) of dental appliance 110 can be created for upper, lower, or upper and lower jaw configurations depending on the requirements of the user.
[0033] One or more sensors are strategically located on inside and/or on the surface of dental appliance 110 . For example, sensors 142 can be located on an extension of a PCB 144 as shown on the embodiment of processor 140 of FIG. 2 .
[0034] Dental appliance 110 can be made from a variety of materials that can vary in flexibility, weight and softness, depending on the intended use. It is also possible for the dental appliance 110 to be semi-customizable, for example, by using a heat-moldable material so that it can be heated to a semi-deformable state, and then placed into a specific user's mouth to semi-permanently conform to the particular user oral contour. Dental appliance 110 can be semi-customizable to include a “Boil & Bite” variety. It is also possible for dental appliance 110 to be fully customizable using molds made of the user's teeth and jaw. Alternate form factors of dental appliance 110 include a low profile device like an orthodontic retainer or similar devices made of a variety of materials including stainless steel, plastics and/or silicon.
[0035] The “Boil & Bite” process for dental appliance can be enhanced by pairing the dental appliance with a dental appliance storage case specifically designed for the requirements of a particular dental appliance design and material composition. The “Boil & Bite” process will aid the user's fit and comfort of the dental appliance.
[0036] To facilitate further discussion, FIG. 9 shows the top, front, and side views of a dental appliance storage case 900 for the monitoring system that includes a base compartment 910 that fits into an outer compartment 912 which holds the base compartment. The dental appliance 110 sits in the base compartment 910 , and base compartment 910 slides into the outer compartment 912 . This storage case attaches through a coupler 913 to other storage cases in order to create a singular stack of storage cases for ease of transportation and ease of organization. This case 900 also serves as a platform for the implementation of the Boil & Bite embodiment described above. The benefits of case 900 includes providing the precise amount of boiling water, protection of the embedded electronic components inside dental appliance 110 while subjected to high heat, and providing a customized user fit. Note that water can be substituted with suitable alternative liquids, including chemical cleaning/disinfecting solutions, known to one skilled in the art.
[0037] Storage Case.
[0038] The storage case 900 may include one or more the following components:
[0039] Base compartment 910 for storing dental appliance 110 .
[0040] Outer compartment 912 for encasing the base compartment 910 . This outer compartment 912 is visually marked with a “water line” 917 notation to provide the user with the proper amount of water to be boiled which gets poured onto the dental appliance 110 . The outer compartment 912 also serves as a cooling tray for the dental appliance 110 to go from the boiling water to an ice bath after a predetermined period of time in the boiling water in the base compartment 910 .
[0041] Pouring spout 914 on the outer compartment 912 which aids in the pouring of the water from the outer compartment 912 into the base compartment 910 onto the dental appliance.
[0042] Detachable, pouring handle 915 on the outer compartment which aids in the handling of the boiling water which is poured onto the dental appliance 110 as it sits in the base compartment 910 .
[0043] Coupler 916 allows the detachable, pouring handle to be removed from the outer compartment 912 to then retrieve the dental appliance 110 from the base compartment 910 after appliance 110 has sat in the base compartment 910 with boiling water thereby further protecting the user from the heated water.
[0044] In some embodiments, dental appliance 1101 can be recharged using an inductive energy (power) transfer, as shown in FIG. 11 . Inductive energy transfer is also known as wireless energy transfer or inductive power capture. The appliance 1101 would be able to be recharged from an inductive power source 1103 that uses an electromagnetic field to transmit power wirelessly from the power source 1103 to the appliance 1101 . Hence, induction coils (not shown) of source 1103 are magnetically coupled to but do not touch the surface of the charger port 1102 of appliance 1101 when appliance 1101 sits on an inductive power source 1103 inside case 1180 . This would enable appliance 1101 to provide body temperature measurements or to be recharged without exposing the electronics of appliance 1101 to outside contaminates.
[0045] As shown in FIG. 12 , in some embodiments, the dental appliance 1200 can be recharged by capturing and converting the energy generated by the user biting down on the appliance 1200 in a normal course of wearing the appliance 1200 in the user's mouth. Normal chewing can generate about 68 lbs./sq. inch of pressure on the back teeth. Clenching teeth may increase that force to about 150 lbs./sq. inch. This energy can be absorbed in devices such as springs 1212 , 1214 and converted into electrical energy to power the appliance 1200 .
[0046] In some embodiments, sensors include temperature sensors. Other sensors suitable for incorporation into monitoring system 100 include without limitation activation sensors, motion sensors, positional sensors, force sensors, optical sensors, radiation sensors, pressure sensors, atmospheric pressure sensors, pulse oximeters capnographs, airflow sensors, alcohol breathalyzers, and/or saliva sensors. Accordingly, user monitoring system 100 and related biometric data processing methods allows the multiplexing of sensors and data processing.
[0047] Activation sensors are useful for managing power requirements and power consumption of the user monitoring system 100 .
[0048] Motion sensors such as gyroscopes and accelerometers are useful for measuring the motion, speed and direction of each user during a training session or game. This data can be used to measure and gauge a variety of measures including the activity level or work rate, fitness level, attentiveness, reaction time, during each game, so real-time feedback can be provided and if necessary corrections can be made and post-activity analysis can be computed. The motion sensor data can be combined with data collected from other sensors such as temperature and respiration to provide a richer biometric profile of the user and/or to alert the user who may be approaching a physical/geographic location to be avoided that includes but is not limited to dangerous, hazardous, or protected areas.
[0049] Positional sensors and/or receivers can assist the observer, e.g., a coach, a trainer, a supervisor, a manager, and/or the user, in tracking the location, the movement, acceleration, and position of the players or workers of his/her team to enhance team cohesion, protection, and effectiveness of the various specialized team members such as soccer players, American football players, military personnel or firefighters. Positional tracking of team members can also minimize, for example, the violation of the “offside” rule of soccer or field hockey or entering restricted zones. The positional sensor data can also be combined with data collected from other sensors such as temperature and respiration to provide a richer biometric profile of the user or to alert the user who may be approaching a zone to be avoided including dangerous, hazardous or protected areas.
[0050] Force sensors such as G-force sensors including accelerometers and gyroscopes are useful for detecting hits directed at the head of the user, and can also be used to compute accumulated potentially concussive hits during each game, or over multiple games. This allows the observer to relieve the user before he/she suffers cumulative brain trauma, thereby substantially increases health and safety in a manner not possible before. Such a feature is especially important in contact sports, the military and emergency personnel where hits to the head are routine such as rugby, American football, soccer, martial arts, and the like. There is medical evidence that cumulative jarring of the brain (short of a concussion that causes loss of consciousness) can, over time, cause permanent damage to the delicate brain issue, including the neurons, nerve interconnections and blood vessels. Force sensors can enable the observer to determine a player's activity level based on the amount of directional change.
[0051] Pressure sensors can detect if the user is biting down with a sufficient amount of force to ensure proper placement of dental appliance 110 thereby ensuring optimal protection of the user's jaw and teeth. One or more pressure sensors can be used to determine whether dental appliance 110 is appropriately positioned for taking accurate biometric and/or environmental data. Accordingly, data acquired before verification of proper positioning may be weighted less or discarded entirely. Pressure sensors can also aid in the rapid detection of medical issues, for example, when user loses consciousness even briefly, or experiences a seizure due to a pre-existing condition and/or due to the sporting/work activity. Pressure sensors can be used to measure grinding of teeth and clenching of the jaw to infer stress. Pressure sensors used in combination with other sensors such as respiration or airflow sensors can increase the data available to detect changes in well-being. Pressure sensors can also be used to identify grinding, clenching, or other states of jaw movement.
[0052] One or more of these sensors, e.g., pressure sensor(s), optical, and/or motion (force) sensor(s), can also be used to detect usage and non-usage for the purpose of system activation and system power conservation. For example, if the dental appliance 110 has been removed, the inactivity indication can be used to trigger a low-power or sleep-mode, thereby extending the life of the power source.
[0053] Optical sensors and/or cameras can also aid to ensure the proper placement of dental appliance 110 , since there should be no substantial gaps between the dental appliance and specific portions of the user's mouth, depending on the type and shape of dental appliance. Optical sensors and/or cameras can also detect if user's mouth is open, partially open, or closed. It may also possible for optical sensors and/or cameras to aid in the measurement of the user's respiration rate, especially if the user is breathing very hard through the mouth.
[0054] To ensure proper functioning of the exemplary sensors described above, especially around the pressure sensors, it is important to keep the dental appliance 110 secured within the user's mouth. Hence methods of improving adhesion to the user's mouth include adhesive microfibers, suction cups, dental adhesive, and a detachable insert for a mouth piece that attaches to the mouth piece bite plate and includes a moldable material for custom forming to the user's teeth on the upper and/or lower jaw.
[0055] In the event that the dental appliance, e.g., dental appliance 110 , of the user is not properly placed, and to further ensure proper functioning of these sensors, an alarm indicator is embedded in the monitoring system 100 enabling the user and/or observer to be notified of such misplacement within the user's mouth or inadequate power for operation of the mouth piece.
[0056] In addition to user safety, all these exemplary sensors described above also provide important data for an analytical toolbox, enabling the user and/or observer to objectively conduct better real time and/or post-event analysis and be able to constructively critique the users' performance based on comprehensive and objective sets of data collected over a period of time. Based on the data collected, assessment, analytical and/or diagnostic strategies can be deployed that define profiles for specific users, a group of users, or the entire population of users to enhance the total system capabilities. Raw and/or processed data can also be aggregated across a broader population to create normative data including body type, nutritional conditions, general well-being, and environmental conditions. Accordingly, data can reside, in whole or in part, locally on a dental appliance, e.g., dental appliance 110 , and/or remotely on an external device, e.g., computerized storage device 840 , or in a variety of locations. The data can also be transferred and shared between user monitoring system(s), e.g., monitoring system 100 , observer monitoring system(s) and/or external storage device(s), device 840 .
[0057] FIG. 7 is a diagram illustrating the one or more customizable functions for the user monitoring system 100 in accordance with the present invention. Based on the user's specific application of use, whether in sports, healthcare, military, or the workplace, the sensors, e.g., activation sensor 710 , motion sensor 720 , . . . saliva sensor 780 , can incorporate diagnostic capabilities and can be used singularly by type or in combination with one or more sensors. Based on the desired configuration, the microprocessor 790 can process raw data, for example, eliminate or scale invalid data point(s), and indicate when data is trending into a known area of concern for that user. Hence, computerized monitoring system 100 can be readily customized based on anticipated usage and desired data to be monitored.
[0058] In some embodiments, computerized monitoring system 100 may also include a transmitter (not shown) coupled to processor 140 , enabling monitoring system 100 to transmit data to an individual user and/or external observer monitoring system (not shown) thereby enabling the individual user and/or user's human observer to receive and analyze user vital signs, biometric data, performance data and environmental data acquired by user monitoring system 100 . External observer monitoring system may be capable of receiving and processing data simultaneously from two or more user monitoring systems. External and/or user monitoring systems may also be capable of receiving and processing data from external sources, such as weather reports, normative data and historical data.
[0059] In some embodiments, the transmitter is located inside the mouth of the user and capable of wirelessly transmitting data directly to the user monitoring system 100 and/or the observer monitoring system. In other embodiments, in order to minimize the signal strength requirements of the transmitter located inside the user's mouth, monitoring system 100 also includes an optional repeater (not shown) which can be worn by the user and incorporated into their uniform, clothing, shoes, or other wearable items, e.g., worn on a belt, worn on a piece of clothing or shoe, incorporated into an ear piece, included as a part of a watch or incorporated into the helmet. The repeater is in relatively close proximity to the dental appliance 110 . This repeater is configured to receive a relatively weak signal from dental appliance 110 and then relay the data at a relatively stronger signal strength to observer monitor system located some distance away, for example, from the playing field to the sidelines or an enclosed viewing booth in a stadium, which can be located up to a couple of hundred yards away. Data can also be acquired and cached by user monitoring system 100 until coupled to or within transmission range of external observer monitoring system.
[0060] In another embodiment, the transmitter is configured to be located outside the mouth of the user, such as in the user's helmet. In this configuration, the transmitter can be coupled to processor 140 via an electrical connection, an optical connection and/or a sonic connection. This connection can be incorporated into an optional tether which can provide mechanical stress and crush protection and also signal shielding.
[0061] In some embodiments, dental appliance 110 also includes one or more visual indicators (not shown) configured to be visible from outside the mouth and may indicate overall statuses. For example, a Green LED may indicate that all user parameters is within a predefined “normal” range for the user, while a Yellow LED may indicate that one or more user parameter is slightly above the “normal” range and may need attention. Conversely, a Red LED may indicate that one or more user parameter is substantially above the “normal” range and needs the immediately attention of the user and/or observer. Fiber optics may be used to reduce power consumption and provide a wider diffusion of visible light on the outward facing edge of dental appliance 110 .
[0062] In addition to or in place of visual indicator(s), monitoring system 100 may include outer indicators that provide non-visual cues such as audible indicators (e.g., a speaker), tactile indicators (e.g., a vibrator) and/or taste-based indicators (e.g., a bitter, sour and/or sweet flavor). The non-visual cues can be low intensity cues intended for the user or higher intensity cues intended for the both the user and the observer.
[0063] It is also possible to provide external power (not shown) to dental appliance 110 via the tether, enabling user to use a larger external power source attached to or incorporated into the user's attire. Potential external power sources include batteries, solar cells and miniaturized fuel cells. It is also possible to recapture energy from the bite forces or head movement of the user. It is also possible to recharge these portable external power sources.
[0064] Referring to FIG. 1 , air channels 112 a , 112 b enable the user to breath in a closed mouth position. These air channels 112 a , 112 b can also aid the insertion of a drinking device such as a hydration tube for the user to consume fluids from an external container such as a bottle (not shown).
[0065] Dental appliance 110 may also include one or more airflow sensors (not shown) proximate to the air channels 112 a , 112 b and configured to measure and send airflow directional data to processor 140 , thereby enabling processor 140 to establish that dental appliance 110 is positioned correctly to collect biometric data accurately as well as to compute a respiration rate of user based on the rhythmic rate of change of airflow direction over time. Alternatively, air pressure sensors (not shown) can be incorporated into dental appliance 110 to measure cyclical changes in air pressure that can then be transposed into a respiration rate for the user. Air volume, direction and pressure data can also be used to infer lung functionality, such as capacity and efficiency. Other portable means for measuring respiration-related biometric data are also contemplated in accordance with the present invention including and not limited to, for example, measuring alcohol level using the user's breath.
[0066] Referring now to FIG. 4 , an exploded view of another embodiment of the user monitoring system 400 illustrating the sub-assemblies: dental appliance 410 , processor 440 , protective cover 450 and disposable media 460 . Dental appliance 410 is coupled to protective cover 450 which include one or more receptacles 455 configured to store and release one or more of a variety of edible and digestible substances, such as nutritional supplements, medications, antibacterial essential oils, spices and herbs, antimicrobial agents, electrolytes, vitamins, stimulants and flavors. The timing and dosage of substance release can be under manual user and/or observer control, such as by using the user's tongue to activate a pressure sensor for a calibrated dose of caffeine or Goo™ when a competitive cyclist is about to ascend a thousand vertical feet. In addition to or in place of manual control, the release schedule and dosage can also be programmed such as in accordance to a medical and/or nutritional program. In addition to a medical and/or nutritional program, this ability to store edible substances enables dental appliance 410 to inhibit the growth of bacteria and the growth of microorganisms which potentially are harmful to the user. Hence, given these examples, it is clearly contemplated that the release of substances can be for a wide variety of nutritional, medical, recreational and/or communicative purposes. Dental appliance 410 can also include a replaceable and disposable strip of media 460 which reacts to saliva in order to provide additional diagnostic assessment information on the user. This replaceable and disposable media strip 460 is a separate optional feature of monitoring system 400 .
[0067] In some embodiments, the user can remove monitoring system 100 from his/her mouth and place dental appliance 110 in close proximity to a docking station (not shown) for downloading data wirelessly or via a connector. The docking system can also serve as a charging station for monitoring system 100 , via for example, an electrical connector or via an inductive coupling.
[0068] In some embodiments, the user monitoring system can be implemented with rechargeable batteries in a manner that allows the user monitoring system to be placed in a storage case, or other recharging station, that includes the ability to conductively and/or inductively charge the user monitoring system. The user monitoring system storage case performs the traditional storage and protection benefits of a standard oral appliance storage case, but also has a design and power source sufficient to recharge one or more batteries and/or user monitoring system(s), as well as facilitate the storage, backup, and/or transmission of data collected by the user monitoring system(s).
[0069] The storage case can also include additional features such as UV light, high temperature steam, or other sterilization technology to clean the user monitoring system(s). The storage case can also include the appropriate sensors to extract and analyze samples of fluids and air samples collected in the user monitoring system while worn in the user's mouth. The storage case can also be used as a hub to receive wired or wireless data from the user monitoring system and/or radio frequency transmission of the data collected on the user monitoring system to an observer monitoring system or another user monitoring system or to a computer network. Docking stations can be in the form of a storage case. Docking stations can also include a multitude of docking bays to charge a plurality of monitoring systems in a team setting.
[0070] In yet another embodiment as illustrated by FIG. 5 , showing user monitoring system 500 , an optional lip protector 560 is operatively coupled to dental appliance 510 , extending outside the user's mouth. Lip protector 560 can include one or more air channels 566 that can also facilitate the use of a drinking device such as a fluid dispensing tube or a more traditional fluid container with a “nib” that controls the fluid flow. The lip protector 560 can be secured by an attachment 567 which is coupled to, e.g., plugs or snaps into, the dental appliance 510 . This attachment 567 acts as a guide for aiding the insertion and removal of dental appliance 510 to and from the user's mouth.
[0071] Lip protector 560 and attachment 567 can also house additional sensors for acquiring environmental data, such as ambient temperature, noise level, humidity and atmospheric pressure. Lip protector 560 and attachment 567 can also house a power source for monitoring system 500 and may also be detachable. In some embodiments, lip protector 560 and the attachment 567 can house processor while the sensors are housed by dental appliance 510 .
[0072] Lip protector 560 can also include a variety of display technologies including lights, alpha numeric displays, graphical displays and audio displays.
[0073] In the case of the very young user and the very old user, the lip protector 560 and attachment 567 can also serve as an aid for placement and removal of dental appliance 510 . An optional external key (not shown) configured to air channels 566 , lip protector 360 , or configured to fit directly to dental appliance 110 can also aid placement and removal of dental appliance 110 to and from the user's mouth.
[0074] In yet another embodiment as illustrated by FIG. 6 , showing user monitoring system 600 includes a dental appliance 610 , configured to fit the user's lower jaw (versus the upper jaw of the user), with a recessed compartment 690 for housing a processor 640 which is shielded by a protective cover 680 .
[0075] Another functional enhancement to user monitoring system(s) is interchangeability between the dental appliances fitting on the upper jaw versus the lower jaw of the user. For certain applications, it may benefit the user to have a single user monitoring system which can be worn in either position. This convertibility and reciprocate ability is contemplated by the present invention.
[0076] In some embodiments, a single user may have more than one user monitoring system depending on the nature of the activity they are performing or a preference for upper versus lower jaw placement in certain situations. Hence, a couple of user monitoring systems may be paired for a specific individual. Accordingly, multiple user monitoring systems designated for a single user may transmit data wirelessly to one or more receiving sources. Data from each of user monitoring systems designated to the single user can be aggregated or maintained separately.
[0077] It can be appreciated that a user does not need to have to have teeth for the user monitoring system to properly function. Hence, in some embodiments, the user who is missing a tooth, multiple teeth or who have removable partials or bridges may attach an optional module, similar in function to a dental bridge, in the user monitoring system's dental appliance configured to fill any of the open space(s) on their gum as they place the dental appliance in their mouth. These modules used singularly or in multiples may act as another pocket for technology components such as sensors. These modules fit in the spaces where a user does not have teeth and/or have removable dental work, and each module would be approximately 3/16″ wide with the ability to slide into place in the dental appliance wherever the user has a gap in their teeth. Whether on the upper or lower jaw of the user, the channel for the teeth on the inside of the dental appliance would create a track for the module to slide and to attach into the proper place on the dental appliance.
[0078] One or more alert devices, such as an audible alarm, can also be incorporated in user monitoring system 100 and/or observer monitoring system. Alerts can be triggered under a wide variety of manual and programmed conditions, such as battery-low-power, data storage overflow warning, insertion of dental appliance 110 prior to competition and removal of dental appliance 110 thereafter, and whenever acquisition of biometric data and/or environmental data is needed.
[0079] Many other functional enhancements to monitoring system 100 and/or observer monitor are also possible. For example, monitoring system 100 can include a transceiver capable of two-way communication instead of a transmitter. Blood oxygenation data may also be collected by monitoring system 100 using optical or other means such as a pulse oximeter or capnograph. Other exemplary enhancements include incorporating microphone(s) and/or speaker(s) thereby enabling the observer and the user to communicate with each other. Microphones can be used in combination with signal processing occurring locally on the user monitoring system or remotely by another processing unit. The data collected by the microphone(s) can be processed to identify the various sounds, categorize the sounds, and/or recognize the events (e.g., speech, snoring, respiration, choking and external noises such as explosion) to infer situational conditions. These categorized sounds can be transmitted to the user and/or other observers. GPS and/or RFID receivers can also be incorporated in monitoring system 100 to provide geographical positional data, enabling a supervisor to track, for example, a team of human fruit pickers.
[0080] Many alternate form factors are also contemplated for user monitoring system 100 and observer monitoring system. For example, the observer monitoring system can be implemented as an application for smart phones, e-books, heart rate monitors, bicycle computers or tablet PCs. The novel concepts of the present invention described above may also be applicable to military personal equipment, workplace protective equipment, and medical devices. In applications where the users are geographically dispersed and/or where transmission obstacles exist (e.g., by a steep canyon wall), networking concepts known to one skilled in the art such as data hopping can also be implemented whereby an intermediate user may relay data from a remote user back to the observer, i.e., function as a repeater.
[0081] With this wealth of user biometric data and environmental data being transmitted by one or more user monitoring systems to the computerized observer monitoring system, many avenues and strategies for analysis and heuristically processes are now possible, including statistical and/or analytical techniques known to one skilled in the data processing arts. Data collected from a wide variety of different sensors can also be used to objectively correlate and cross-validate data, thereby increasing the reliability and accuracy of the data collected. Such processing workload can either be assigned to one or more of user monitoring system 100 , the observer monitoring system, and a remote processing system. As discussed above, FIG. 8 illustrates the user monitoring system(s) 811 , 812 , . . . 819 and observer monitoring system 820 collecting and sharing biometric and environmental data via a two-way means of communication. Such an embodiment 800 allows real-time data collection, sharing and aggregation.
[0082] For example, temperature sensors can be used in a variety of creative ways. For example, “normal” user temperature profiles can be developed for individual users during active and relative inactive periods. These “normal” profiles can serve as an early warning system that enables the observer to pay attention to the user before significant deterioration of the user's health or performance occurs. Profiles can also be developed based on other sensors types. Combinational profiles can also be developed based on multiple sensor types. It is also possible to further adapt these user profiles to accommodate many different environmental factors and also clothing worn by the user. Examples of factors and clothing include climate, ambient temperature, humidity, chemicals present in the air, changes in air pressure, elevation of the geographical location and clothing apparel and accessories such as insulated helmets, shoes, and other protective gear.
[0083] Once placed in the mouth and positioned properly, presets can be applied for each user based on normative data within a specific user and/or across the user population. The user monitoring system can use the presets as the beginning data point in calculating the data trending and data averaging methods benefitting the user and can be used for other functions including defining custom notification thresholds.
[0084] Caloric burn rate can be inferred from such temperature readings over time. Temperature readings can also be used to as a guide to hydration strategies, to minimize the occurrence of extreme heat related conditions such as heat exhaustion and heat strokes. Conversely, temperature readings can also be used as a guide to rest periods in a heated area to minimize the occurrence of extreme cold conditions such as frost bites.
[0085] The user monitoring system in accordance with the present invention can assess when a user's temperature rises substantially close to or over 100 degrees Fahrenheit which further promotes safety for that user and/or observer. Accordingly, a fever resulting in an elevated temperature can be the early warning sign of an infection that may need medication to address the infection. This data becomes very important in the consistent monitoring of cancer patients where their immune system is already compromised by cancer treatments such as chemotherapy, radiation and immunotherapy. Further, a body temperature above 100 degrees Fahrenheit may also be a sign of a concussion, and once a concussive event is suspected, an elevated temperature is a condition that is watched for in the user and/or observer. Further, measuring body temperature over time can be used to track the ovulation cycle of females.
[0086] Sleep disturbances can also affect a user's temperatures and the user monitoring system can help monitor temperature fluctuations during sleep that may be caused by sleep apnea, insomnia, and other sleep disorders.
[0087] To improve the efficiency and accuracy of data analysis, it is also possible to preload processor 140 and/or individual observer monitor system and/or observer monitor system with initial preset limits and profiles for generic users, individualized athlete profiles and for specific activities. Preloading can be very advantageous since specific activities and specific team-roles can impose very different demands on the user. For example, a mixed martial artist has very different demands from that of a speed skater, and a soccer goal keeper's activities are very different from that of a defender. Similarly, an American football quarterback's physical and mental demands are very different from that of an offensive lineman.
[0088] To further improve the efficiency and accuracy of data analysis, it is also possible to correlate and to factor the variations in temperature that result in circadian rhythm, time of day, and other circumstances affecting a user's temperature.
[0089] By comparing data from multiple sensors of the same type, and/or across sensors of different types, it is also possible to cleanse data by detecting and partially or fully omitting aberrant data from, for example, malfunctioning or misaligned sensors. Data cleansing can be implemented in real-time or during post-activity analysis. Data cleansing can also applied across multiple data sets acquired during several separate activities.
[0090] To further protect the user monitoring system electronics which gather and process data, a potting material can be wrapped around the microprocessor and related components to provide a method of encapsulation of these components. This encapsulation further protects the user's tissue and tongue while the dental appliance is worn. This creates a technology capsule that can be placed in the dental appliance. The potting material can also enhance the ability of the electronics to withstand the high temperatures inherent in the injection molding process for manufacturing dental appliances.
[0091] In yet another embodiment of this present invention, an independent external module can be attached to an existing user's dental appliance such as a mouth guard that an individual already owns. Hence the ability to adapt “after-market” technology module that can be attached to an existing oral appliance through multiple ways consistent with the form factor of the existing oral appliance. Methods of attachment include rubber posts, adhesive and technology module adapter which allow the supplemental technology module to enhance the functionality of an existing user monitoring system. This flexibility also enables independent modules to be reused or repurposed as accessories between different dental appliances.
[0092] FIG. 10 illustrates an exemplary embodiment applicable to an athlete 1000 and related observer 1020 . With dental appliance 1010 worn by athlete 1000 , observer 1020 can monitor biometric data gathered by dental appliance 1010 and transmitted to receiver 1030 . To minimize the signal strength requirements of the transmitter located inside the athlete's mouth, the monitoring system can include a repeater 1040 .
[0093] In some embodiments, the user monitoring system deploys an extension of the temperature algorithm to recognize the operational effectiveness of the user body's ability to dissipate heat, thereby using the core body temperature to determine if the user is recovering from an unusual rise in core body temperature. There are generally four primary ways the user's body can dissipate heat: conduction (i.e., skin touching something cooler), convection (i.e., cooler air currents touching the body), radiation (i.e., radiating electromagnetic waves leaving the user's body), and evaporation (i.e., sweating). Radiation accounts for 50-65% of heat loss and evaporation accounts for 30-35% of heat loss. Radiation becomes ineffective once the user's body's core temperature reaches 35 degrees Celsius, and evaporation ceases to be effective at 100% humidity (body covered in sweat). Thus, there are times when human activity will cause the body's core temperature to rise, and the body's systems are unable to dissipate the heat. Thus, in addition to calculating the core body temperature, monitoring the core body temperature and knowing when the body is no longer recovering, it indicates the individual is in danger besides the absolute temperature number. For example, a user may no longer be dissipating heat when their core body temperature is 39 degrees Celsius (slightly above normal), but the user needs to cease their activity or they will enter heat exhaustion and potentially heat stroke. Thus, the user monitoring system is able to measure the effects of normal core body temperature fluctuations of the user (i.e., “continuously calculated temperature variations”) and recognize when the user is not fluctuating on their “normal” basis.
[0094] In another embodiment, the dental appliance can include pulse oximeter technology as illustration in FIG. 13 . As shown in FIG. 13 , the pulse oximeter 1300 consists of a light source 1301 and a photodetector 1302 which reads through the vascular bed of a user's gum. Pulse oximeter technology can be used to enhance performance and protection by providing a measurement of a variety of conditions including the oxygen saturation in the blood and changes in blood volume, assist in detection of when ventilation is inadequate to perform necessary gas exchange in the lungs (hypoventilation), estimate heart rate by measuring cyclic changes in light transmission, and is a biomarker for diagnosis of sleep apnea.
[0095] In another embodiment, the dental appliance can include capnograph technology as illustrated in FIG. 14 . As shown in FIG. 14 , the non-invasive capnograph technology 1400 can be used to enhance performance and protection by providing a monitoring of a variety of variables including the amount of carbon dioxide in the expired air. The capnograph sensor 1401 monitors CO2 production as well as respiratory patterns. Too much carbon dioxide would suggest that the gas exchange in the lungs is not functioning.
[0096] In another embodiment, receptacles built into the dental appliance can also capture exhaled air. This captured air can be processed in real time or post event using mass spectrometry to identify the conditions of the user's body. Monitoring and analyzing expelled air during breathing with a dental appliance can be used for a variety of biometric monitoring including detection of problems of oxygen and carbon dioxide exchange in the lungs, the presence of drugs such as alcohol, and other biomarkers such as aldehydes which indicate a variety of circumstances including oxidative stress due to excessive exercise.
[0097] The receptacles could be in a variety for forms including a channel with collection area within the dental appliance, a closed receptacle that is operated manually by user biting pressure on the dental appliance that mechanically opens the receptacle, by electromechanical means initiated by the user at a preset time or as initiated by a remote communication received through a transceiver located on the dental appliance. The channel and/or receptacle can also include a membrane or absorbent material that collects the samples. Processing of the samples can occur on the dental appliance and/or remotely.
[0098] As shown in FIG. 4 , uses of the receptacles include salivary sampling and assessment of a user's pH and their saliva viscosity. This aids in monitoring a user's hydration level/status and provides a diagnostic tool for potential early detection of health related problems associated with a wide array of human conditions including; but not limited to, dehydration, poor dental care, unhealthy balance between acid and alkaline seen through a user's pH, poor digestive enzyme activity, harmful bacteria detection, indication of recent illegal drug use and identification of medical allergies.
[0099] While this invention has been described in terms of several embodiments, there are alterations, modifications, permutations, and substitute equivalents, which fall within the scope of this invention. Although sub-section titles have been provided to aid in the description of the invention, these titles are merely illustrative and are not intended to limit the scope of the present invention.
[0100] It should also be noted that there are many alternative ways of implementing the methods and apparatuses of the present invention. It is therefore intended that the following appended claims be interpreted as including all such alterations, modifications, permutations, and substitute equivalents as fall within the true spirit and scope of the present invention.
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Methods to prevent harm to athletes from overexertion, including inserting a dental appliance into a mouth of each monitored athlete, the dental appliance having sensors for monitoring parameters such as body temperature and hydration level of the athlete. Obtaining at a monitoring station wireless transmissions of current measurements from each of the dental appliances. Storing measurements along with a source of the measurements and a time associated with the measurements. Providing a notification when a monitored athlete is in danger from overexertion as indicated by a trend in the stored measurements.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of and claims the benefit of priority under 35 U.S.C.§120 to U.S. patent application Ser. No. 14/957,598, filed on Dec. 3, 2015, which is a continuation of and claims the benefit of priority under 35 U.S.C.§120 to U.S. patent application Ser. No. 14/113,640, filed on Oct. 24, 2013, which is a U.S. National Stage Application filed under 35 U.S.C.§371 of International Application Serial No. PCT/US2012/035241, filed Apr. 26, 2012, and published on Nov. 1, 2012 as WO 2012/149179, which claims priority of U.S. provisional application no. 61/479,038, filed Apr. 26, 2011, each of which applications and publication are herein incorporated by reference in their entireties.
FIELD OF THE INVENTION
The invention relates to a process for bonding a silicone or silicone based material to a polyurethane and use of the bonded silicone-polyurethane in the manufacture of biomaterials, devices, articles or implants, in particular long term implantable medical devices in the fields of cardiology, orthopaedics, plastic surgery and gastroenterology.
BACKGROUND OF THE INVENTION
Silicone medical device components have the advantages of high flexibility and biostability. However, they also possess the disadvantage of being relatively weak in their mechanical properties such as tensile strength and abrasion resistance. Frequently a surface layer of a high abrasion resistant material is required above a substrate of a silicone device. Polyurethanes offer that high abrasion resistance and other good mechanical properties.
However, some of the properties of polyurethanes make the combination of silicone and polyurethane components difficult.
Most commercial polyurethanes are not biostable and tend to break down under in-vivo conditions in long term implantation.
Biostable polyurethanes are disclosed in WO92/00338, WO98/013405, WO95/5424, WO99/003863, WO99/050327, WO00/6497 and WO2007/112485 including ELAST-EON 2 (AORTECH BIOMATERIALS, Victoria, Australia) which is a polyurethane having a soft segment based on 80 wt % of a hydroxyl terminated polydimethylsiloxane (PDMS) and 20 wt % of a polyether polyol specifically polyhexamethylene oxide (PHMO). These polymers are stable under in-vivo conditions and can been used for many long term implantable applications.
Bonding of silicone based components to polyurethane based components has been tried using several methods. Treating the surface of silicone with a primer, use of glues and plasma treatments have been employed and these methods deliver a bond with certain degree of adhesiveness. However, in many applications the bond has proven to be inadequate. The bonding of most materials to silicone is a challenge due to the low surface energy of silicone. In fact silicone sprays are used in mould releases and moulds can be constructed from silicones to provide good release of mouldings.
SUMMARY OF THE INVENTION
We have now found that altering the surface of the silicone can lead to significant changes in the adhesive properties of the silicone.
In one aspect, there is provided a process for bonding a silicone or a silicone based material to a polyurethane which comprises the steps of:
(a) flame treating a surface of the silicone or silicone based material; and (b) bonding the polyurethane to the flame treated surface of the silicone or silicone based material.
In another aspect, there is provided a silicone or a silicone based material when bonded to a polyurethane by the process defined above.
In a further aspect, there is provided a biomaterial, device, article or implant which is wholly or partly composed of the silicone or a silicone based material when bonded to a polyurethane by the process defined above.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention involves flame treating a surface of a silicone or silicone based material and bonding a polyurethane to the flame treated surface of the silicone. While not wishing to be bound by any theory, it is believed that this high temperature flame treatment leads to the formation of oxides on the surface of the silicone and these oxides react with the isocyanate and NCO groups on the polyurethane.
Silicone or Silicone-based Material
The term “silicone” as used herein refers to silicone or silicone based solids of varying hardness including elastomers, rubbers and resins. The hardness may be in the range of 10 to 90 Shore A. These polymers include silicons together with carbon, hydrogen and oxygen. Silicones are also known as polymerised siloxanes or polysiloxanes composed of units having the formula (R) 2 SiO in which R is an organic side chain which is not hydrogen. Representative examples are [Si(CH 3 ) 2 O] n (polydimethylsiloxane) and [Si(C 6 H 5 ) 2 O] n (polydiphenylsiloxane) in which n is an integer of 1 or greater. The compounds can be viewed as a hybrid of both organic and inorganic compounds. The organic side chains confer hydrophobic properties while the —Si—O—Si—O— backbone is purely inorganic. Examples of silicones or silicone-based materials include silicone rubber, coatings, encapsulants and sealants.
Polyurethane
The polyurethane is preferably biostable for use as a biomaterial in medical devices, articles or implants. Suitable biostable polyurethanes include polyurethanes, polyurethane ureas or polycarbonates containing silicon. Examples of silicon-containing polyurethanes, polyurethane ureas or polycarbonates include those disclosed in WO92/00338, WO98/13405, WO98/54242, WO99/03863, WO99/50327, WO00/64971 and WO2007/112485, the entire contents of which are incorporated herein by reference. The polyurethanes, polyurethane ureas or polycarbonates generally contain a soft segment and a hard segment. The segments can be combined as copolymers or as blends. For example, polyurethanes with soft segments such as PTMO, polyethylene oxide, polypropylene oxide, polycarbonate, polyolefin, polysiloxane (for example polydimethylsiloxane) and other polyether soft segments made from higher homologous series of diols may be used. Mixtures of any of the soft segments may also be used. The soft segments also may have either alcohol end groups or amine end groups. The molecular weight of the soft segments may vary from about 500 to about 6000. It will be understood that the molecular weight values referred to herein are “number average molecular weights”.
Suitable polyether diol and diamine soft segments include those represented by the formula (I)
A-[(CH 2 ) m —X] n -A′ (I)
in which
A is OH or NHR, X is O or NR and A′ is H wherein R is H or optionally substituted C 1-6 alkyl, more preferably optionally substituted C 1-4 alkyl;
m is an integer of 4 or more, preferably 4 to 18; and
n is an integer of 2 to 50.
Preferably polyether diol soft segments include those represented by formula (I) wherein A is OH and A′ is H.
Polyether diols of formula (I) wherein m is 4 to 10 such as polytetramethylene oxide(PTMO), polyhexamethylene oxide (PHMO), polyheptamethylene oxide, polyoctamethylene oxide (POMO) and polydecamethylene oxide (PDMO) are preferred. PHMO is particularly preferred.
The preferred molecular weight range of the polyether is 200 to 5000, more preferably 200 to 2000.
Suitable polycarbonate diols include poly(alkylene carbonates) such as poly(hexamethylene carbonate) and poly(decamethylene carbonate); polycarbonates prepared by reacting alkylene carbonate with alkanediols for example 1,4-butanediol, 1,10-decanediol (DD), 1,6-hexanediol (HD) and/or 2,2-diethyl 1,3-propanediol (DEPD); and silicon based polycarbonates prepared by reacting alkylene carbonate with 1,3-bis(4-hydroxybutyl)1,1,3,3-tetramethyldisiloxane (BHTD) and/or alkanediols.
It will be appreciated when both the polyether and polycarbonate macrodiols are present, they may be in the form of a mixture or a copolymer. An example of a suitable copolymer is a copoly(ether carbonate) macrodiol represented by the formula (II)
in which
R 1 and R 2 are the same or different and selected from an optionally substituted C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, arylene or a heterocyclic divalent radical; and
p and q are integers of 1 to 20.
Although the compound of formula (II) above indicates blocks of carbonate and ether groups, it will be understood that they also could be distributed randomly in the main structure.
Suitable polysiloxane diols or diamines are represented by the formula (III):
in which
A and A′ are OH or NHR wherein R is H or optionally substituted C 1-6 alky, more preferably optionally substituted C 1-4 alkyl;
R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen or optionally substituted C 1-6 alky;
R 15 and R 16 are the same or different and selected from optionally substituted C 1-6 alkylene, C 2-6 alkenylene, C 12-6 alkynylene, arylene or a heterocyclic divalent radical; and
p is an integer of 1 or greater.
A preferred polysiloxane is a hydroxyl terminated PDMS which is a compound of formula (III) in which A and A′ are hydroxyl, R 11 to R 14 are methyl and R 15 and R 16 are as defined above. Preferably R 15 and R 16 are the same or different and selected from propylene, butylene, pentylene, hexylene, ethoxypropyl (—CH 2 CH 2 OCH 2 CH 2 CH 2 —), propoxypropyl and butoxypropyl, more preferably ethoxypropyl. A particularly preferred polysiloxane is Shin Etsu product X-22-160AS having a molecular weight of 947.12 which is α-ω-bis(bydroxyethoxypropyl)polydimethylsiloxane.
Other silicon-containing diols of the formula (III) are 1,3-bis(4-hydroxybutyl)tetramethyl disiloxane (BHTD) (compound of formula (III) in which A and A′ are OH, R 11 , R 12 , R 13 and R 14 are methyl, R 15 and R 16 are butyl and p is 1), 1,4-bis(3-hydroxypropyl)tetramethyl disilylethylene (compound of formula (III) in which A and A′ are OH, R 1 , R 12 , R 13 and R 14 are methyl, R 15 and R 16 are propyl, p is 1 and O is replaced by ethylene) and 1-4-bis(3-hydroxypropyl)tetramethyl disiloxane, more preferably BHTD.
The polysiloxanes may be obtained as commercially available products such as X-22-160AS from Shin Etsu in Japan or prepared according to known procedures. The preferred molecular weight range of the polysiloxane macrodiol is 200 to 6000, more preferably from 200 to 5000.
Other preferred polysiloxanes are polysiloxane macrodiamines which are polymers of the formula (III) wherein A is NH 2 , such as, for example, amino-terminated PDMS.
Suitable silicon-containing polycarbonates have the formula (IV):
in which
R 11 , R 12 , R 13 , R 14 and R 15 are as defined in formula (III) above;
R 16 is an optionally substituted C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, arylene or a heterocyclic divalent radical;
R 17 is a divalent linking group, preferably O, S or NR 18 ;
R 18 and R 19 are same or different and selected from optionally substituted C 1-6 alkyl;
A and A′ are as defined in formula (III) above;
m, y and z are integers of 0 or more; and
x is an integer of 0 or more.
Preferably z is an integer of 0 to 50 and x is an integer of 1 to 50. Suitable values for m include 0 to 20, more preferably 0 to 10. Preferred values for y are 0 to 10, more preferably 0 to 2.
A preferred silicon-containing polycarbonate is a compound of the formula (IV) in which A and A′ are hydroxyl.
Particularly preferred silicon-containing polycarbonate diols are compounds of the formula (IV) in which A and A′ are hydroxyl, R 11 , R 12 , R 13 and R 14 are methyl, R 18 is ethyl, R 19 is hexyl, R 15 and R 16 are propyl or R 14 butyl and R 17 is O or —CH 2 —CH 2 —, more preferably R 15 and R 16 are propyl when R 17 is O and R 15 and R 16 are butyl when R 17 is —CH 2 —CH 2 —. The preferred molecular weight range of the silicon-based polycarbonate macrodiol is from 400 to 5000, more preferably from 400 to 2000.
Preferably, the hard segment is formed from a diisocyanate and a chain extender.
The diisocyanate may be represented by the formula OCN—R—NCO, where —R— may be aliphatic, aromatic, cycloaliphatic or a mixture of aliphatic and aromatic moieties. Examples of diisocyanates include 4,4′-diphenylmethane diisocyanate (MDI), methylene biscyclohexyl diisocyanate (H 17 MDI), tetramethylene diisocyanate, hexamethylene diisocyanate, trimethyhexamethylene diisocyanate, tetramethylxylylene diisocyanate such as p-tetramethylxylene diisocyanate(p-TMXDI) or m-tetramethylxylene-diisocyanate (m-TMXDI), 4,4′-dicyclohexylmethane diisocyanate, dimer acid diisocyanate, isophorone diisocyanate (IPDI), metaxylene diisocyanate, diethylbenzene diisocyanate, decamethylene 1,10 diisocyanate, cyclohexylene 1,2-diisocyanate, trans-cyclohexylene-1,4-diisocyanate (CHDI). 2,4-toluene diisocyanate (2,4-TDI), 2,6-toluene diisocyanate, xylene diisocyanate, p-phenylene diisocyanate (p-PDI), m-phenylene diisocyanate (m-PDI), hexahydrotoylene diisocyanate (and isomers), naphthylene-1,5-diisocyanate (NDI), 1-methoxyphenyl 2,4-diisocyanate, 4,4′-biphenylene diisocyanate, 3,3′-dimethoxy-4,4′-biphenyl diisocyanate or 1,6-diisocyanatehexane (DICH), isomers or mixtures thereof. Preferably the diisocyanate is MDI.
The term “chain extender” in the present context means any chain extender which is capable of reacting with a diisocyanate group. The chain extender generally has a molecular weight range of 500 or less, preferably 15 to 500, more preferably 60 to 450 and may be selected from diol or diamine chain extenders.
Examples of diol chain extenders include C 1-12 alkane diols such as 1,4-butanediol (BDO), 1,6-hexanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol and 1,12-dodecanediol; cyclic diols such as 1,4-cyclohexanediol. 1,4-cyclohexanedimethanol, 1,4-bis(2-hydroxyethoxy)benzene and p-xyleneglycol; and silicon-containing diols such as 1,3-bis(4-hydroxybutyl) tetramethyldisiloxane and 1,3-bis(6-hydroxyethosypropyl) tetramethyldisiloxane. Preferably the diol chain extender is BDO.
The diol chain extender may also contain silicon. Suitable silicon-containing diol chain extenders include those of formula (V)
in which
R 1 , R 2 , R 3 and R 4 are the same or different and selected front H and an optionally substituted C 1-6 alkyl;
R 5 and R 6 are the same of different and selected from optionally substituted C 1-6 alkylene, C 2-6 alkenylene, C 12-6 alkynylene, arylene and a heterocyclic divalent radical;
R 7 is a divalent linking group, preferably O; and
n is 0 or greater, preferably 2 or less.
Suitable diamine chain extenders include C 1-12 alkane diamines such as 1,2-ethylenediamine, 1,3-propanediamine, 1,4-butanediamine and 1,6-hexanediamine: and silicon-containing diamines such as 1,3-bis(3-aminopropyl) tetramethyldisiloxane and 1,3-bis(4-aminobutyl)tetramethyldisiloxane.
The diamine chain extender may also contain silicon. Suitable silicon-containing diamine chain extenders include those of formula (VI)
in which
R is hydrogen or an optionally substituted C 1-6 alkyl;
R 1 , R 2 , R 3 and R 4 are the same or different and selected from hydrogen and optionally substituted C 1-6 alkyl;
R 5 and R 6 are the same or different and selected from optionally substituted C 1-6 alkylene, C 2-6 alkenylene, C 12-6 alkynylene, arylene and a heterocyclic divalent radical;
R 7 is a divalent linking group, preferably O; and
n is 0 or greater, preferably 2 or less.
Other applicable biostable polyurethanes include those using polyol as a component of the hard segment. Polyols may be aliphatic, aromatic, cycloaliphatic or may contain a mixture of aliphatic and aromatic moieties. For example, the polyol may be ethylene glycol, diethylene glycol, triethylene glycol, 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, propylene glycols, 2,3-butylene glycol, dipropylene glycol, dibutylene glycol glycerol, or mixtures thereof. Polyurethanes modified with cationic, anionic and aliphatic side chains may also be used (see, for example, U.S. Pat. No. 5,017,664).
It will be appreciated that polyurethanes which are not biostable may also be used in the process of the present invention as they are intended to be bonded to silicone or silicone based materials which are biostable and are therefore still suitable for use in medical devices, articles or implants.
Examples of polyurethanes which are not biostable include polyester polyol based polyurethanes and also polyurethanes with limited biostability such as those based on polyether polyols.
The bonding process has been found to be particularly advantageous when the polyurethane is applied to the flame treated silicone surface in the form of a liquid such as in a solvent or as a reactive liquid. Suitable solvents include organic solvents such as dimethyl acetamide (DMAc), dimethyl formamide (DMF) and tetrahydrofuran (THF).
Flame Treatment
Any known flame treatment may be used to oxidise at least part of the surface of the silicone or silicone based material. The range of suitable parameters for the flame treatment are as follows: the oxygen ratio (%) detectable after combustion from 0.05% to 5%, preferably from 0.2% to 2%; treatment speed from 0.1 m/min to 2000 m/min, preferably from 10 m/min to 100 m/min; treatment distance from 1 mm to 500 mm, preferably from 2 mm to 50 mm. Many gases are suitable for flame treatment including natural gases; pure combustible gases such as methane, ethane, propane and hydrogen; or a mixture of different combustible gases. The combustion mixture also includes air, pure oxygen or oxygen containing gases.
The surface of the silicone is preferably treated with a blue flame at temperatures in the range of 1550° C. to 3000° C. and the resultant surface has an excellent adhesion with the polyurethane. The flame treatment may be performed using any suitable known apparatus such as a burner based on natural gas such as propane, butane or methane. The flame treatment should be done with care and only for a short time such as 2 to 10 seconds as excessive and improper treatment can lead to burning of the silicone. The flame treatment may be repeated several times to ensure adecuate bonding of the polyurethane. Once the polyurethane has been bonded to the silicone, then the bonded silicone-polyurethanes can be cured to further promote bonding if necessary.
Applications
The bonded silicone-polyurethanes of the present invention are particularly useful in preparing biomaterials and medical devices, articles or implants as a consequence of their biostability, acid resistance and abrasion resistance and mechanical properties including tensile modulus and creep resistance.
The term “biostable” refers to a stability when in contact with cells and/or bodily fluids of living animals or humans.
The term “biomaterial” refers to a material which is used in situations where it comes into contact with the cells and/or bodily fluids of living animals or humans.
The medical devices, articles or implants may include catheters; stylets; bone suture anchors; vascular, oesophageal and bilial stents; cochlear implants; reconstructive facial surgery; controlled drug release devices; components in key hole surgery; biosensors; membranes for cell encapsulations; medical guidewires; medical guidepins; cannularizations; pacemakers, defibrillators and neurostimulators and their respective electrode leads; ventricular assist devices; orthopaedic joints or parts thereof including spinal discs and small joints; cranioplasty plates; intraocealar lenses; urological stents and other urological devices; stent/graft devices; device joining/extending/repair sleeves; heart valves; vein grafts; vascular access posts; vascular shunts; blood purification devices; casts for broken limbs; vein valve, angioplasty, electrophysiology and cardiac output catheters; plastic surgery implants such as breast implant shells; lapbands; gastric balloons; and tools and accessories for insertion of medical devices, infusion and flow control devices.
It will be appreciated that polyurethanes having properties optimised for use in the construction of various medical devices, articles or implants will also have other non-medical applications. Such applications may include toys and toy components, shape memory films, pipe couplings, electrical connectors, zero-insertion force connectors, Robotics, Aerospace actuators, dynamic displays, flow control devices. sporting goods and components thereof, body-conforming devices, temperature control devices, safety release devices and heat shrink insulation.
Example
The Invention will now be described with reference to the following non-limiting example.
An implantable orthopaedic device had a section coated with silicone. This section had to be overmoulded with Elast-Eon2 in order to prevent the abrasion of the bottom layer and thus the malfunctioning of the device.
A flame was lit on a propane gas based blow torch. The silicone portion was treated with the blue past of a flame. The treatment process was ˜2 seconds a pass over the silicone portion and there were three passes in total. The flame was at a distance of ˜5 mm from the device.
An Elast-Eon2 mixture was then prepared by mixing a pre-polymer containing α-ω-bis(hydroxyethoxypropyl)polydimethylsiloxane (Shin Etsu product X-22-160AS, MW 947.12), polyhexamethyleneoxide (PHMO) and 4,4′-diphenylmethane diisocyanate (MDI) with 1,4-butane diol (BDO). As this mix was ready, it was drawn out in a syringe and injected over the treated silicone surface. The entire device was then placed in a mould and cured for an hour before demoulding. The device, after demoulding, was further cured for 10 hours in an oven with a temperature of 100° C.
All publications, patents and patent applications are incorporated herein by reference. While in the foregoing specification this invention has been described in relation to certain preferred embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein may be varied considerably without departing from the basic principles of the invention.
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The invention relates to a process for bonding a silicone or silicone based material to a polyurethane and use of the bonded silicone-polyurethane in the manufacture of biomaterials, devices, articles or implants, in particular long term implantable medical devices in the fields of cardiology, orthopaedics, plastic surgery and gastroenterology. The process involves the steps of (a) flame treating a surface of the silicone or silicone based material and (b) bonding the polyurethane to the flame treated surface of the silicone or silicone based material.
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This application is a continuation of application Ser. No. 09/640,382, filed Aug. 17, 2000, now abandoned.
FIELD OF THE INVENTION AND RELATED ART
The present invention relates to an image forming apparatus which forms an image on recording medium by ejecting liquid such as ink from a printing head, and a pump for such an image forming apparatus.
In an image forming apparatus such as an ink jet printer, ink is ejected from the ejection orifices of a printing head to form an image on a piece of recording medium. During the operation of such an image forming apparatus, ink (with increased viscosity), dust, and the like, adhere to the ejection orifices of the printing head. Thus, in order to remove these contaminants, an ink jet printer is generally provided with a recovery means to keep stable the ink ejection performance of the printer.
A recovery means generally comprises a capping means, a wiping means, and a pumping means. The capping means comprises a plurality of caps for covering the printing head, across the surface with ejection orifices, while the apparatus is not recording. It prevents ink from drying or evaporating while the apparatus is not recording. The wiping means comprises a blade or the like for removing the ink adhering to the printing head surface with ejection orifices. The pumping means suctions the ink with increased viscosity, and the like, from the ejection orifices and their adjacencies, through the capping means.
Generally speaking, a conventional pumping means comprises a cylinder and a piston which shuttles within the cylinder, with its peripheral surface remaining in contact with the internal surface of the cylinder. Technology regarding such a pumping means is disclosed in Japanese Laid-Open Patent Application No. 067,121/1998.
FIG. 18 is a schematic sectional drawing which presents an example of a conventional pumping means for an image forming apparatus. As depicted in FIG. 18, the pumping means comprises a cylinder 160 , and a piston 164 which shuttles within the cylinder 160 . The cylinder 160 is provided with two ink suction holes 161 and 162 and one ink discharge hole 163 . The ink suction holes 161 and 162 are connected to two capping members (unillustrated), one for one.
When the pumping means structured as described above is in operation, the piston 164 shuttles within the internal space of the cylinder 160 , with its peripheral surface remaining in contact with the internal surface of the cylinder 160 . As the piston 164 shuttles, ink is suctioned into the cylinder 160 through the ink suction holes 161 and 162 , and then is discharged from the cylinder 160 through the ink discharge hole 163 as a common ink discharge hole. This pumping means is superior in space utilization efficiency, compared to a pumping means which comprises two caps, and two cylinders parallelly disposed corresponding one for one to the two caps. In other words, this pumping means has an advantage over the latter, in that it makes it possible to reduce the overall size of an image forming apparatus.
However, the pumping means structured as described has a problem. That is, after the ink is suctioned into the cylinder, the ink is left alone to discharge itself out of the cylinder by its own weight. As a result, a certain amount of ink remains within the cylinder. If the ink which is remaining in the cylinder adheres to the internal surface of the cylinder and solidifies there, there is a possibility that the gap between the cylinder and piston fails to be properly sealed. If the gap fails to be properly sealed, air is allowed to leak through the gap, causing the pumping means to fail to properly suction ink. There is also a possibility that the ink will remain between the cylinder and piston and solidifies there. If the ink which is remaining between the cylinder and piston solidifies, the force required to make the piston slide on the internal surface of the cylinder sometimes becomes large enough to prevent the piston from being driven, which results in ink suction failure.
SUMMARY OF THE INVENTION
A principal object of the present invention is to provide an image forming apparatus pump which does not suffer from leakage and waste liquid solidification which lead to suction failure, and to provide an image forming apparatus equipped with such a pump.
Another object of the present invention is to provide an image forming apparatus pump capable of easily discharging waste liquid, and to provide an image forming apparatus equipped with such a pump.
According to an aspect of the present invention, there is provided an image forming apparatus comprising cap members for capping ejection outlets of an ejection portions for ejecting liquid to a recording material; pump means including suction inlets in fluid communication within said cap members; discharging outlets for discharging the liquid; cylinder means including a plurality of cylinders having said suction inlets and said discharging outlets, respectively; a seal member for dividing inner space in the cylinder means into said cylinders; and a plurality of pistons reciprocable in the spaces in contact with the inner surfaces of the cylinders to produce pressure change in the inner spaces; wherein in each of said cylinders, said suction inlet is disposed more away from seal member than said discharging outlet.
According to another aspect of the present invention, there is provided a pump for an image forming apparatus which includes cap members for capping ejection outlets of an ejection portions for ejecting liquid to a recording material, said pump comprising suction inlets in fluid communication within said cap members; discharging outlets for discharging the liquid; cylinder means including a plurality of cylinders having said suction inlets and said discharging outlets, respectively; a seal member for dividing inner space in the cylinder means into said cylinders; and a plurality of pistons reciprocable in the spaces in contact with the inner surfaces of the cylinders to produce pressure change in the inner spaces; wherein in each of said cylinders, said suction inlet is disposed more away from seal member than said discharging outlet.
As described above, according to the present invention, an image forming apparatus pump comprises a plurality of cylindrical portions which are provided with the suction hole or holes and discharge hole or holes, and are aligned in a straight line; a single or plural sealing members which serve as a divider between the internal spaces of the adjacent two cylinder portions, and a plurality of pistons which shuttle within the correspondent cylinder portions, with the peripheral surface thereof remaining in contact with the internal surfaces of the cylinder portions, to change the internal pressures of the cylinder portions. After being suctioned into the internal spaces of the plurality of cylinder portions, liquid is almost completely discharged through the discharge holes by the pressure generated in the space between the pistons and correspondent sealing members. In other words, according to the present invention, it is possible to prevent leakage and solidification of waste liquid, which lead to suction failure, by reducing the amount of the liquid which remains in the cylinder.
Further, the present invention eliminates the need for arranging a plurality of the cylinder portions in parallel corresponding to a plurality of capping member, making it possible to reduce the overall size and cost of an image forming apparatus.
Further, according to the present invention, in each cylinder portion, the suction hole is disposed on the far side, with respect to the discharge hole, from the sealing member, making it possible to place the discharge holes closer to each other to make it easier to dispose waste liquid.
Further, according to the present invention, a plurality of rings are on the peripheral surface of each of the plurality of pistons so that only the peripheral surfaces of the rings make contact with the internal surface of each cylinder portion, reducing the size of the contact area between the internal surface of the cylinder and the peripheral surface of the piston. Therefore, even if liquid enters between the internal surface of a cylinder portion and a piston, and solidifies there, it does not occur that liquid fails to be satisfactorily suctioned due to the insufficiency in the piston driving force.
Further, according to the present invention, among the plurality of the rings on the peripheral surface of each of the plurality of pistons, the ring on the upstream side in terms of the direction in which the piston moves for suctioning is rendered greater in external diameter than the ring on the downstream side, equalizing both rings in their contact pressure upon the internal surface of the cylinder portion to prevent leakage. Therefore, liquid is reliably suctioned.
In addition, the force required to drive the pistons is smaller, making it possible to employ a motor, or the like, with relatively low torque as a driving force source to reduce noise level compared to when a high torque motor is employed.
These and other objects, features, and advantages of the present invention will become more apparent upon consideration of the following description of the preferred embodiments of the present invention, taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is an external perspective view of the image forming apparatus in an embodiment of the present invention.
FIG. 2 is a schematic plan view of the sheet conveyance mechanism for conveying the sheets placed in the sheet feeder tray illustrated in FIG. 1, onto the platen illustrated in FIG. 1 .
FIG. 3 is an external perspective view of the driving mode switching means illustrated in FIG. 1, and depicts the structure of the driving mode switching means.
FIG. 4 is a plan view of the driving mode switching means illustrated in FIG. 3 .
FIG. 5 is a plan view of the right side of the driving mode switching means illustrated in FIG. 3 .
FIG. 6 is a sectional view of the pumping means illustrated in FIG. 3, and depicts the structure of the pumping means.
FIG. 7 is a drawing for describing the operational sequence through which ink is suctioned into, or discharged from, the cylinder 516 illustrated in FIG. 6 .
FIG. 8 is a drawing for describing the operational sequence through which ink is suctioned into, or discharged from, the cylinder 517 illustrated in FIG. 6 .
FIG. 9 is a schematic drawing for describing the shape of the piston illustrated in FIG. 6 .
FIG. 10 is a graph for describing the relationship between the external diameter D 1 of the ring portion 519 a illustrated in FIG. 9, and the contact pressure P 1 applied by the ring portion 519 a upon the cylinder 517 , and the relationship between the external diameter D 1 of the ring portion 519 a and the contact pressure P 2 applied by the ring portion 519 b upon the cylinder 517 .
FIG. 11 is a plan view of the adjacencies of the joint between the pumping means and capping means illustrated in FIG. 3 .
FIG. 12 is a sectional view of the capping means illustrated in FIG. 11 .
FIG. 13 is a plan view of the front side of the driving mode switching means illustrated in FIG. 3 .
FIG. 14 is a plan view of the left side of the driving mode switching means illustrated in FIG. 3 .
FIGS. 15, ( a ) and ( b ), are graphs for describing the movements of the capping means, carriage lock, and P sensor transmission lever, with respect to the rotational angle of the P output gear illustrated in FIG. 3, and the movement of the ink suctioning movement of the pumping means with respect to the rotational angle of the P output gear, respectively.
FIG. 16 is a perspective view of a head cartridge integrally comprising a printing head and an ink container; FIGS. (a), (b), and (c) correspond to a black cartridge, a color cartridge, and a photographic cartridge.
FIG. 17 is a perspective view of the essential portion of an ink jet recording head in accordance with the present invention, with some portions, omitted.
FIG. 18 is a schematic sectional view of an example of a conventional pumping means to be placed in an image forming apparatus, and depicts the structure of the pumping means.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Hereinafter, the preferred embodiments of the present invention will be described with reference to the appended drawings.
FIG. 1 is an external perspective view of the image forming apparatus in an embodiment of the present invention. FIG. 2 is a plan view of the sheet conveyance mechanism for conveying the sheets placed in the sheet feeder tray 101 illustrated in FIG. 1, onto the platen 301 illustrated in FIG. 1 .
FIG. 16 is a perspective view of a head cartridge integrally comprising a printing head and an ink container. In FIG. 16, FIGS. (a), (b), and (c), correspond to a black cartridge, a collar cartridge, and a photographic cartridge. The number of ejection orifices is different for a black head, a color head, and a photographic head, and will be described later in detail. These printing heads are optionally mounted on a carriage 201 ; one of them is mounted according to the printing objective.
FIG. 17 is a perspective view of the essential portion of one of the image forming apparatuses in accordance with the present invention, with some portions omitted. The top member of an ink jet recording head H ( 400 ) is made of resinous material, and integrally comprises: a top plate portion, in which a liquid chamber 1104 for storing recording liquid, and a plurality of liquid paths, are formed; an ejection outlet plate portion 1101 , in which a plurality of ejection orifices 1102 correspondingly connected to the plurality of liquid paths 1103 are formed; and a recording liquid receiving portion 1105 . A heater board 1107 comprises: a substrate formed of silicone; a plurality of heaters (electrothermal transducers) 1106 , which are aligned on the silicone substrate to generate the thermal energy to be used for causing the so-called film boiling in the ink to eject ink; and unillustrated wiring for supplying these heaters with electrical power. These heaters and the wiring are formed by a known film formation technology. The heater board 1107 is fixed to a base plate 1110 by a known die bonding technology. The wiring substrate 1108 is provided with the wiring connected to the wiring of the heater board 1107 by a known wire bonding technology, and with a plurality of pads 1109 which are positioned one for one at both ends of the wiring to receive electrical signals from the main assembly of the image forming apparatus. The top plate 1100 and heater board 1107 are bonded to each other, with the plurality of the liquid paths 1103 and heaters 1106 aligned one for one to each other, and are fixed to the base plate 1110 , along with the wiring substrate 1108 , forming the ink jet recording head H.
Referring to FIGS. 1 and 2, the image forming apparatus in this embodiment comprises: a sheet feeder roller 102 for conveying the sheets (medium on which recording is made) placed in a sheet feeder tray 101 ; a conveyer roller 302 for conveying the sheets onto the platen 301 after the sheets are fed into the apparatus by the sheet feeder roller 102 ; a carriage 201 on which a printing head comprising a portion from which ink is ejected, and an ink container 203 , are mounted; a rail 360 on which the carriage 201 is slidably supported to be shuttled in the longitudinal direction of the rail 360 ; a recovery means for restoring the performance of the plurality of printing heads mounted on the carriage 20 ; a driving mode switching means 600 driven by the conveyer roller 302 ; and a chassis 350 .
In an image forming apparatus structured as described above, as the sheets placed in the sheet feeder tray 101 are conveyed onto the platen 301 by the sheet feeder roller 102 and conveyer roller 302 , ink is ejected onto the sheets from the plurality of printing heads on the carriage 201 which are being shuttled on the rail 360 . As a result, an image is formed on the sheets.
Next, the sheet feeder mechanism, illustrated in FIG. 1, for conveying the sheets from the sheet feeder tray 101 onto the platen 301 will be described.
The rotational force from a pulse motor 305 is transmitted by way of a speed reduction gear 306 to a conveyer gear 303 fixed to one of the longitudinal ends of the conveyer roller 302 , in order to rotate the conveyer roller 302 .
On the other hand, an LF output gear 304 is fixed to the other end of the conveyer roller 302 . Therefore, the rotational force transmitted to the conveyer roller 303 is transmitted to the recovery means and sheet feeder gear 105 disposed within a switching means 600 , by way of the LF output gear 30 .
As the driving force is transmitted to the sheet feeder gear 105 , the sheet feeder roller 102 rotates, and the sheets placed in the sheet feeder tray 101 are conveyed to the conveyer roller 302 by the rotation of the sheet feeder roller 102 . After being conveyed to the conveyer roller 302 , the sheets are conveyed onto the platen 301 by the conveyer roller 302 .
Next, the driving mode switching means 600 illustrated in FIG. 1 will be described in detail.
FIG. 3 is an external perspective view of the driving mode switching means 600 illustrated in FIG. 1, and depicts the structure of the driving mode switching means 600 . FIG. 4 is a plan view of the driving mode switching means 600 illustrated in FIG. 3, and FIG. 5 is a plan view of the right side of the driving mode switching means 600 illustrated in FIG. 3 .
As shown in FIGS. 3-5, in order to prevent the drying or evaporation of ink, the printing head in this embodiment is provided with a capping means comprising caps 528 and 529 for capping the printing head surface which has the ejection orifices. The caps 528 and 529 are selectively activated depending on the configuration of the printing head surface which has ejection orifices. Further, the image forming apparatus in this embodiment is provided with a recovery means 500 , which comprises a pumping means 503 and a wiping means 502 . The pumping means 503 suctions ink, and the like, from the ejection orifices and the adjacencies thereof. The wiping means 502 removes the ink adhering to the printing head surface with ejection orifices, using of a blade (unillustrated). The capping means 501 and pumping means 503 are driven as the driving force is transmitted to the P output gear 604 and piston gear 510 from the LF output gear 304 (FIG. 2 ).
The P output gear 604 is a gear rotationally fitted around a P output gear shaft 509 , the longitudinal ends of which are supported by a driving mode switching means base 601 .
Further, the P output gear 604 comprises: a cam portion 604 b for regulating the vertical movement of a carriage lock 511 which is under the pressure generated in the direction of the carriage 201 (FIG. 1) by a pressure generating means 543 such as a spring, and also, for regulating the phase of the toothless portion of the P outlet gear 604 ; a cam portion 604 c for regulating the vertical movement of the caps 528 and 529 ; and a cam portion (unillustrated) for regulating a P sensor transmission lever 512 which engages with a P sensor lever (unillustrated), which detects the rotational angle of the cam 604 c.
Next, the sequential steps through which the driving force from the LF output gear 304 (FIG. 2) is transmitted to the P output gear 604 and piston gear 510 will be described.
After being transmitted to an LF transmission gear 602 meshed with the LF output gear 304 , the driving force is transmitted to a P clutch gear 630 , by way of the LF transmission gear 602 , a transmission shaft 605 , and a P transmission gear 606 .
When the pumping means 503 is driven, and immediately after the capping means 503 begins to be driven, a P clutch trigger gear 632 is slid by the carriage 201 (FIG. 1 ), whereby the latchet portion of the P clutch trigger gear 632 is meshed with the latchet portion of the P clutch gear 630 .
Therefore, when the pumping means 503 is driven, and immediately after the capping means 503 begins to be driven, the driving force transmitted to the P transmission gear 606 is transmitted to the P output gear 604 , and then is transmitted to the piston gear 510 , rotating the piston gear 510 .
The P output gear 604 is provided with a toothless portion, which is on the P clutch gear 630 side. Thus, when the pumping means 503 is not being driven, that is, when the sheets are being fed, when the sheets are discharged, when images are being printed, and when the like operations are carried out, the P output gear 604 is not in mesh with the P clutch gear 630 .
Therefore, the driving force from the LF output gear 304 is transmitted to the P output gear 604 , as the P output gear 604 is meshed with the P clutch gear 630 or P clutch trigger gear 632 when the pumping means 503 is driven, or immediately after the capping means 503 begins to be driven.
Next, the pumping means 503 illustrated in FIG. 3 will be described in detail.
FIG. 6 is a sectional view of the pumping means 503 illustrated in FIG. 3, and depicts the structure of the pumping means 503 .
As shown in FIG. 6, the pumping means 503 in this embodiment comprises: a cylinder portion 516 (which hereinafter may be simply called “cylinder”) provided with an ink suction hole 516 a and an ink discharge hole 516 b ; a cylinder portion 517 (which hereinafter may be simply called “cylinder”) provided with an ink suction hole 517 a and an ink discharge hole 517 b ; a sealing member 523 which is disposed between washers 522 and 524 , being sandwiched by them, and serves as the divider between the cylinder portions 516 and 517 ; pistons 518 and 519 which shuttle within the cylinder portions 516 and 517 , respectively; and a piston shaft 513 which supports the pistons 518 and 519 .
In this embodiment, as the driving force from the piston gear 510 is transmitted to the piston shaft 513 , the pistons 518 and 519 supported by the piston shaft 513 shuttle. As a result, ink is suctioned into the cylinder portions 516 and 517 through the ink suction holes 516 a and 517 a , and then is discharged through the discharge holes 516 b and 517 b by the pressure generated between the piston 518 and sealing member 523 , and between the piston 519 and sealing member 523 , respectively.
The surface of the center hole of the piston gear 510 has a guide portion 510 a , so that the driving force from the piston gear 510 is transmitted to a screw portion 513 a through the guide portion 510 a in order to cause the piston shaft 513 to shuttle in the horizontal direction.
The piston shaft 513 is provided with a piston stopper 520 and a stopper rubber 521 for regulating the movement of the piston 518 .
Between the cylinder portion 517 and cylinder cap 515 , a sealing member 526 and a washer 525 are sandwiched.
The piston shaft 513 is provided with a guide pin 514 , which has been pressed into a hole 513 b with which the piston shaft 513 is provided. The guide pin 514 shuttles along a guide portion 515 a with which the cylinder cap 515 is provided, preventing the piston shaft 513 from rotating.
Also, in order to prevent the piston shaft 513 from rotating, a projection (unillustrated) on the cylinder cap 515 is engaged in a recess (unillustrated) in the cylinder portion 517 .
Next, the ink suctioning and discharging operations of the pumping means structured as described above will described in detail.
FIG. 7 is a drawing for describing the processes through which ink is suctioned or discharged by the pumping means. At this time, the sequential steps will be described with reference to the cylinder portion 516 .
As the piston 518 passes by the ink suction hole 516 a , while moving from the initial position (FIG. 7, ( a )) toward the ink discharge hole 516 b , ink 591 is suctioned into the cylinder portion 516 by the accumulated negative pressure through the ink suction hole 516 a . As the amount of the ink 591 reaches a predetermined value, the piston 518 stops there (FIG. 7 ( b )).
Next, the moving direction of the piston 518 reverses; the piston begins to move toward the initial position illustrated in FIG. 7, ( a ) (FIG. 7 ( c )). During this movement of the piston 518 , the ink 591 , which has been suctioned into the cylinder portion 516 , moves toward the ink discharge hole 516 b through the ink path provided between the piston 518 and piston shaft 513 . The piston 518 moves to the end of its stroke (FIG. 7, ( d )).
Next, the piston 518 begins to move toward the ink discharge hole 516 b . As the piston 518 moves, the ink 591 , which has moved toward the ink discharge hole 516 b , is forcefully discharged through the ink discharge hole 516 b by the pressure generated as the space between the sealing member 523 sandwiched by the washers 522 and 523 , and piston 518 becomes less (FIG. 7, ( e )).
Thereafter, the piston 518 shuttles a predetermined number of times (dry strokes). As the piston 518 goes through the dry strokes, the ink within the cylinder 516 is almost completely discharged through the ink discharge hole 516 b.
The position from which the piston 518 begins to move, and the position of the other end of the piston stroke, may be varied depending on printing head type (in terms of color, capacity, and the like), so that the amount by which ink is suctioned into the cylinder portion is optimized, depending on the printing head type.
FIG. 8 is a drawing for describing the processes through which ink is suctioned into, or discharged from, the cylinder 517 illustrated in FIG. 6 .
Since the processes through which ink is suctioned into, or discharge from, the cylinder portion 517 are the same as those for the cylinder portion 516 , the detailed description thereof will be omitted.
As shown in FIG. 6, there are a few internal spaces in the cylinder portion 517 . One of the longitudinal ends of the piston shaft 513 is in the left most internal space in the cylinder portion 517 . With this arrangement, the aforementioned leftmost internal space is greater in volume than the rightmost internal space in the cylinder portion 517 . The leftmost and rightmost internal spaces are connected to the relatively large cap 528 (FIG. 3 ), and the relatively small cap 529 (FIG. 3 ), respectively. The relatively large cap 528 and relatively small cap 529 are used to cap a color ink head (FIG. 16) which is relatively large in the total number of ejection orifices, and a black ink head (FIG. 16) which is relatively small in the total number of ejection orifices, respectively. In this embodiment, the color ink head comprises 48 ejection orifices for black ink, 48 ejection orifices for cyan ink, 48 ejection orifices for magenta ink, and 48 ejection orifices for yellow ink, totaling 192 ejection orifices. The black ink head has 160 ejection orifices. In other words, a head having the greater number of ejection orifices to be capped is capped with the relatively large cap, which is connected to the cylinder portion larger in the volume of the internal space into which ink is suctioned. This is because it is desired that the greater a printing head is in the total number of ejection orifices to be capped together, the larger the amount of liquid to be suctioned must be, so that ejection orifices are equalized in the amount of the ink suctioned through them. The photographic head is the same as the color ink head in the total number of ejection orifices. In other words, the photographic ink head is provided with 48 ejection orifices for photographic black ink, 48 ejection orifices for photographic cyan ink, 48 ejection orifices for photographic magenta ink, and 48 ejection orifices for photographic yellow ink, totaling 192 ejection orifices. The photographic ink head is capped by the cap 528 , that is, the same cap as the one for the color ink head, and is suctioned by the leftmost most portion of the cylinder, which is relatively large in the internal space.
In this embodiment, in order to make the color ink head and photographic ink head greater in the total amount of suction than the black ink head, the pumping means is structured so that the length of the stroke of the piston 518 between the position from which the piston 518 begins to move, and the position of the other end of the stroke, can be adjusted depending on head type. In other words, the length of the stroke of the piston 518 is made greater when the color ink head or photographic ink head is suctioned than when the black ink head is suctioned.
Next, the pistons 518 and 519 illustrated in FIG. 6 will be described in detail.
FIG. 9 is a drawing for describing the configurations of the pistons 518 and 519 illustrated in FIG. 6 . At this time, the description will be given with reference to the piston 519 .
Referring to FIG. 9, the piston 519 is provided with ring portions 519 a and 519 b , which are on the peripheral surface of the piston 519 , and are the only portions of the piston 519 which make contact with the internal surface of the cylinder portion 517 .
With the provision of the above described structure, the size of the contact area between the piston 519 and the internal surface of the cylinder portion 517 is smaller than when the piston 519 is not provided with the rings 519 a and 519 b.
Therefore, even if the piston 519 is caused to temporarily stick to the cylinder portion 517 by the ink which has solidified in the gap between the cylinder portion 517 and piston 519 after flowing into the gap, the force required to loosen the piston 519 from the cylinder portion 517 is smaller, making this structural arrangement advantageous in that it is unlikely to make the pumping means 503 impossible to drive.
The relationship among the external diameter D 1 of the ring portion 519 a , the external diameter D 2 of the ring portion 519 b , and the internal diameter D 3 of the cylinder portion 517 is: D 3 <D 2 <D 1 . In other words, the ring portion 519 a with the external diameter of D 1 , which is on the upstream side in terms of the direction in which the piston 519 is moved to suction ink, is greater in the external diameter than the ring portion 519 b with the external diameter of D 2 , which is on the downstream side.
This structural arrangement is made so that the contact pressure P 1 between the ring portion 519 a and cylinder portion 517 remains the same as the contact pressure P 2 between the ring portion 519 b and cylinder portion 517 while the piston shaft 513 moves in the cylinder portion 517 in the direction indicated by an arrow mark A, that is, the ink suctioning direction.
As the piston shaft 513 moves in the direction of the arrow mark A, a reactive force P, the direction of which is opposite to the direction of the arrow mark A, applies to the piston 519 due to the friction between the internal surface of the cylinder portion 517 and the peripheral surface of the piston 519 . This sometimes causes the deformation of the piston 519 , which makes the contact pressure P 1 smaller than the contact pressure P 2 .
In the above described situation, the piston 519 becomes unstable, threatening to increase the possibility that suction failure or the like will occur due to leakage.
The piston 518 is also provided with ring portions, which are on the peripheral surface of the piston 518 . The external diameter D 1 of the ring portion located on the upstream side in terms of the direction in which the piston 518 moves to suction ink is greater than the external diameter of the ring portion on the downstream side.
Next, the relationship between the external diameter D 1 of the ring portion 519 a and the contact pressure P 1 , and the relationship between the external diameter D 1 of the ring portion 519 a and the contact pressure P 2 , will be described.
FIG. 10 is a drawing for describing the relationship between the external diameter D 1 of the ring portion 519 a illustrated in FIG. 9 and the contact pressure P 1 of the ring portion 519 a upon the cylinder 517 , and the relationship between the external diameter D 1 of the ring portion 519 a and the contact pressure P 2 of the ring portion 519 b upon the cylinder 517 .
FIG. 10 represents a case in which the value of the internal diameter D 3 of the cylinder portion 517 , and the value of the external diameter D 2 of the ring portion 519 b , were preset so that the external diameter D 2 of the ring portion 519 b became larger than the internal diameter D 3 of the cylinder portion 517 , and only the external diameter D 1 of the ring portion 519 a was varied.
As shown in FIG. 10, as the external diameter D 1 of the ring portion 519 a was varied from a small size to a larger size, the contact pressure P 1 increased, whereas the contact pressure P 2 decreased. Eventually, the contact pressures P 1 and P 2 became equal to each other at a point at which the value of the external diameter D 1 was “Q (>external diameter D 2 )”.
In other words, the contact pressures P 1 and P 2 can be rendered equal to each other by setting the value of the external diameter D 1 of the ring portion 519 a to “Q”, so that the piston 519 can be stabilized in its shuttling movement.
Next, the positional relationship between the pumping means 503 and capping means 501 illustrated in FIG. 3 will be described, along with the structure of the capping means 501 .
FIG. 11 is a plan view of the joint between the pumping means and capping means 501 illustrated in FIG. 3, and its adjacencies. FIG. 12 is a sectional view of the cap 529 illustrated in FIG. 11 .
The capping means 501 is rotationally supported. More specifically, the caps 528 and 529 are fixed to a cap holder 527 provided with two bosses. The two bosses are fitted one for one in the hole of an arm portion 516 c integrally formed with the cylinder portion 516 and the hole of the arm portion 517 c integrally formed with the cylinder portion 517 .
The cap holder 527 has two positioning bosses 527 a and 527 b , in addition to the aforementioned two bosses. These bosses 527 a and 527 b are fitted in a groove (unillustrated) which is U-shaped in cross section and with which the base 601 (FIG. 4) is provided.
Further, the cap holder 527 is provided with a hole 527 c as a positioning hole in which the boss portion (unillustrated) of the base 601 is fitted.
The cap 528 is provided with a tube portion 528 a , which is integrally formed with the cap 528 . This tube portion 528 a is connected to the ink suctioning portion, in the form of a projection, with which the cylinder portion 516 is provided; the tube portion 528 a is press-fitted around the projection.
The cap 528 has an internal absorbent member 530 for absorbing and retaining the ink within the cap 528 .
The cap 529 has a tube portion 529 a , which is integrally formed with the cap 529 . This tube portion 529 a is connected to the ink suctioning portion, in the form of a projection, with which the cylinder portion 517 is provided; the tube portion 529 a is press-fitted around the projection.
Further, the cap 529 has an internal absorbent member 531 for absorbing and retaining the ink within the cap 529 .
The pumping means 503 is rotationally supported by the base 601 . More specifically, the shaft portion 510 b of the piston gear 510 is fitted in the hole of the base 601 , and the shaft portion 516 d of the cylinder portion 516 is fitted in the hole of a bearing 532 (FIG. 4) with which the base 601 is provided.
The pumping means 503 is under the pressure applied from the back side of the cap holder 527 , in the direction to rotate the pumping means 503 , by the spring 544 (FIG. 5) with which the base 601 is provided.
An arm portion 517 d is an integrally formed portion of the cylinder portion 517 , and regulates the rotation of the pumping means 503 , in coordination with the cam portion 604 c (FIG. 4) of the P output gear 604 (FIG. 4 ).
While the pumping means 503 suctions ink, the cap 528 or 529 is kept in contact with the printing head mounted on the carriage 201 (FIG. 1 ). The amount of the pressure with which the cap 528 or 529 is pressed upon the printing head is set at a predetermined value.
Also during this period, the arm portion 517 d remains separated from the cam portion 604 c of the P output gear 604 .
Next, the wiping means 502 illustrated in FIG. 3 will be described in detail.
FIG. 13 is a plan view of the front side of the driving mode switching means 600 illustrated in FIG. 3 . FIG. 14 is a plan view of the left side of the driving mode switching means 600 illustrated in FIG. 3 .
FIG. 13 shows the state of the driving mode switching means 600 , in which the wiping means 502 , disposed within the driving mode switching means 600 , is at the wiping position for wiping the printing head mounted on the carriage 201 (FIG. 1 ).
First, referring to FIGS. 13 and 14, the steps for setting the wiping means 502 in the driving mode switching means 600 , at the wiping position, and the steps for disengaging the wiping means 502 , will be described.
As a B trigger lever 532 is moved in the direction of an arrow mark B by the movement of the carriage 201 , the cam portion (unillustrated) of the B trigger lever 532 engages with the boss portion 534 b of a B lever 534 , causing the B lever 534 to move in the direction of an arrow mark E.
The B lever 534 is between the base 601 and a base cover 640 , being sandwiched between them.
A B lock 536 is rotationally supported by the B lever 534 . As the B lever 534 rotates at a predetermined angle, the B lock 536 slides onto the projecting portion of the base 601 , becoming locked in order to complete the steps for setting the wiping means 502 for wiping.
The B lock release lever 538 is a lever for dissolving the locked state of the B lock 536 . As the carriage 201 moves in the direction of an arrow mark C after the completion of the wiping operation, the carriage 201 comes into contact with the B lock release lever 538 , causing the B lock release lever 538 to move in the direction of an arrow mark F. As a result, the B lock 536 rotates in the lock releasing direction, allowing the B lever 534 to be set at the no-wiping position by a pressure generating means 535 such as a spring placed between the base 601 and B lever 534 , dissolving the state in which the wiping means 502 is ready for wiping.
Next, the structure of the wiping means 502 will be described.
Referring to FIGS. 13 and 14, the wiping means 502 has blades 541 a and 541 b for removing the ink adhering to the printing head surface with the ejection orifices, a B holder 539 which supports the blades 541 a and 541 b through a spacer (unillustrated), and supports a B retainer 542 for retaining the B holder 539 . The B holder 539 is under pressure generated in the direction of an arrow mark G by a pressure generating means 540 such a spring placed between the B holder 539 and the B lever 534 .
In the wiping operation of the wiping means 502 structured as described above, the striking surface 539 a of the B holder 539 comes in contact with the bottom surface of the carriage 201 to control the amount of the overlap between the surface (with the ejection orifices) of the printing head mounted on the carriage 201 , and the blades 541 a and 541 b , so that the surface (with the ejection orifices) of the printing head is properly wiped by the blades 541 a and 541 b.
FIG. 15 is a graph for describing the movements of the various components disposed within the driving mode switching means, with respect to the rotational angle of the P output gear 604 illustrated in FIG. 3; Figure (a) depicts the movements of the capping means 501 , a carriage lock 511 (FIG. 4 ), and the P sensor transmission lever 512 (FIG. 3 ), and Figure (b) depicts the ink suctioning movement of the pumping means 503 .
The P output gear 604 can be rotated either forward or in reverse within a range of 0°-330°. The rotational angle of 0° corresponds to the home position, which is used as the referential position for the capping operation of the capping means 501 , for the ink suctioning operation of the pumping means 503 , and for the like operations.
For example, when ink is suctioned by the pumping means 503 through the cap 528 , the P output gear 604 rotates in reverse from the position corresponding to a rotational angle of 299° to the position corresponding to a rotational angle of 82°, whereas when ink is suctioned through the cap 529 , the P output gear 604 rotates forward from the position corresponding to a rotational angle of 35° to a position corresponding to a rotational angle of 250°.
In terms of the rotational angle, the position from which the P output gear 604 begins to rotate, and the position at which it stops rotating, correspond to the amount of ink to be suctioned into the cylinder portions during the ink sucking strokes of the pistons and during the dry strokes of the pistons, and also correspond to the amount of the negative pressure which applies to the printing head while ink is suctioned. The pumping means 503 is provided with a plurality of operational modes inclusive of the number of pumping strokes to be repeated for ink suction and virtually dry suction, so that an optimal operation mode is selected from among the plurality of operation modes according to the aforementioned factors.
While the invention has been described with reference to the structures disclosed herein, it is not confined to the details set forth and this application is intended to cover such modifications or changes as may come within the purposes of the improvements or the scope of the following claims.
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An image forming apparatus includes cap members for capping ejection outlets of an ejection portions for ejecting liquid to a recording material; pump diviec including suction inlets in fluid communication within the cap members; discharging outlets for discharging the liquid; cylinder member including a plurality of cylinders having the suction inlets and the discharging outlets, respectively; a seal member for dividing inner space in the cylinder divice into the cylinders; and a plurality of pistons reciprocable in the spaces in contact with the inner surfaces of the cylinders to produce pressure change in the inner spaces; wherein in each of the cylinders, the suction inlet is disposed more away from seal member than the discharging outlet.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is related to the following concurrently filed U.S. patent applications: “Tool with articulation lock” of Hegeman, Danitz, Hinman, and Alvord, “Tool with force limiter” of Hinman and Bertsch, “Tool with rotation lock” of Hinman and Danitz, and “Articulating tool with improved tension member system” of Hegeman, Danitz, Bertsch, and Alvord.
INCORPORATION BY REFERENCE
[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
FIELD OF THE INVENTION
[0003] This invention relates to tools with end effectors whose actuators may be operated in multiple different operation states.
BACKGROUND OF THE INVENTION
[0004] The popularity of minimally invasive surgery has been growing rapidly due to its association with decreased complication rates and post-surgical recovery times. The instruments employed are generally hand-operable and typically include a handle, a shaft that may or may not be rotatably attached to the handle, a rotation knob rigidly fixed to the proximal end of the shaft near the handle in instances where the shaft is rotatably attached to the handle, and a tool or end effector attached to the distal end of the shaft. To manipulate the instruments, they are held at the handle and typically pivoted about a pivot point defined by the entry incision, i.e., the incision made in the abdominal wall for laparoscopic procedures. The end effector may also be rotated about the shaft axis, as for example, by rotating a rotation knob, if present. In use, these instruments have limited control and range of motion and become physically taxing as the length of the procedure increases.
[0005] Surgical procedures such as endoscopy and laparoscopy typically employ instruments that are steered within or towards a target organ or tissue from a position outside the body. Examples of endoscopic procedures include sigmoidoscopy, colonoscopy, esophagogastroduodenoscopy, and bronchoscopy, as well as newer procedures in natural orifice transluminal endoscopic surgery (“NOTES”). Traditionally, the insertion tube of an endoscope is advanced by pushing it forward, and retracted by pulling it back. The tip of the tube may be directed by twisting and general up/down and left/right movements. Oftentimes, this limited range of motion makes it difficult to negotiate acute angles (e.g., in the rectosigmoid colon), creating patient discomfort and increasing the risk of trauma to surrounding tissues.
[0006] Laparoscopy involves the placement of trocar ports according to anatomical landmarks. The number of ports usually varies with the intended procedure and number of instruments required to obtain satisfactory tissue mobilization and exposure of the operative field. Although there are many benefits of laparoscopic surgery, e.g., less postoperative pain, early mobilization, and decreased adhesion formation, it is often difficult to achieve optimal retraction of organs and maneuverability of conventional instruments through laparoscopic ports. In some cases, these deficiencies may lead to increased operative time or imprecise placement of components such as staples and sutures.
[0007] Recently, surgical instruments, including minimally invasive surgical instruments, have been developed that are more ergonomic and which have a wider range of motion and more precise control of movement. These instruments may include mechanisms that articulate using a series of links coupled with one or more sets of tension bearing members, such as cable. As with conventional instruments used in minimally invasive surgery, rotation of the shaft and end effector with respect to the handle is an important feature of cable and link type instruments to aid with dissecting, suturing, retracting, knot tying, etc. Ergonomic, flexible, and intuitive mechanisms that facilitate manual control of the end effectors of such instruments are also important factors as medical procedures become more advanced, and as surgeons become more sophisticated in operating abilities. Further improvements in the features and design of surgical instruments are desirable.
SUMMARY OF THE INVENTION
[0008] Embodiments of the invention include a shaft having a proximal end and a distal end, an end effector at the distal end of the shaft, a movable end effector actuator at the proximal end of the shaft and operably connected to the end effector, and an actuator movement controller operably connectable to the end effector actuator. The actuator movement controller includes a user-activated state changer that is changeable among several states. These states include ones in which the movement controller is (1) enabled and engaged with the end effector actuator to prevent movement of the end effector actuator in at least one of two opposing directions, (2) enabled and disengaged from the end effector actuator to permit movement of the end effector actuator in a first direction and a second direction opposite to the first direction in response to continuous user input via the state changer, and (3) disabled to permit movement of the end effector actuator in a first direction and a second direction opposite to the first direction in the absence of user input via the state changer. In some embodiments, the first state (enabled and engaged) may prevent movement of the end effector actuator in both directions.
[0009] In some embodiments the end effector includes jaws. In some embodiments the actuator movement controller includes a ratchet. In some embodiments the state changer includes a movable trigger. In some embodiments with a trigger, the state changer further includes a toggle operatively connected to the trigger so as to be movable with the trigger and to be rotatable with respect to the trigger. In some of the embodiments with a toggle, the toggle is operatively connected to the trigger so as to move with the trigger without rotating with respect to the trigger when the movement controller is enabled.
[0010] In some embodiments where the toggle is so-connected to the trigger, surgical instrument further includes a handle at the proximal end of the shaft, and the trigger is supported by the handle, and is movable with respect to the handle. The toggle is disposed within the handle, and the trigger may include a toggle-camming surface and the toggle may include trigger-camming surface complementary-to and engagable with the trigger surface. The handle of some embodiments may include a toggle guide, operatively connected to the toggle, to guide movement of the toggle. Engagement of the complementary camming surfaces of the trigger and toggle respectively, due to movement of the trigger creates a rotational force between the trigger and toggle.
[0011] Embodiments summarized immediately above may further include a wing extending radially from a toggle body, the handle toggle guide comprising a slot in which the toggle wing is disposed to prevent rotation of the toggle as the toggle moves with the trigger. The handle's toggle guide may include a handle canning surface complementary-to, and engagable with the toggle wing's camming surface such that engagement of the handle camming surface with the toggle wing's camming surface creates a rotational force between the handle and the toggle. In such embodiments, the toggle may have a range of motion, and the handle toggle guide may be adapted to prevent rotation of the toggle in a first portion of the toggle's range of motion and to permit rotation of the toggle with respect to the trigger in a second portion of the toggle's range of motion. The toggle may further include a wing extending radially from a toggle body, the handle toggle guide include a slot in which the toggle wing is disposed when the toggle is in the first portion of its range of motion, the toggle wing being outside the slot when the toggle is in the second portion of its range of motion
[0012] Returning to the movable trigger, in some embodiments the trigger is movable from a first position in which the movement controller is enabled and engaged to a second position in which the movement controller is enabled and disengaged. The trigger may be further movable to a third position in which the movement controller is disabled. In such embodiments with the third position, the trigger may be further movable so as to enable and engage a disabled movement controller. The movement controller may further include a state change notifier that is operatively connected to the trigger and adapted to provide notice of an impending change in movement controller state that will be caused by further movement of the trigger. The state change notifier is adapted to provide tactile feedback to a user through the trigger of an impending change in movement controller state that will be caused by further movement of the trigger; such tactile feedback may include an increased level of resistance to movement of the trigger.
[0013] Embodiments of the invention include a shaft having a proximal end and a distal end, an end effector at the distal end of the shaft, a movable end effector actuator at the proximal end of the shaft and operably connected to the end effector, and an actuator movement controller operably connectable to the end effector actuator. The actuator movement controller may include a state changer and a biasing member. The state changer may be movable against the biasing member in response to a user input from a first state in which the movement controller is enabled and engaged with the end effector actuator to permit movement of the end effector actuator in one direction and prevent movement of the end effector actuator in an opposite direction to a second state in which the movement controller is enabled and disengaged from the end effector actuator to permit movement of the end effector actuator in a first direction and a second direction opposite to the first direction. The biasing member may be operably connected with the state changer to move the state changer from the second state to the first state when the user input ceases or diminishes.
[0014] In some embodiments, as summarized above, the state changer may be movable against the biasing member in response to a user input from the second state to a third state in which the movement controller is disabled to permit movement of the end effector actuator in a first direction and a second direction opposite to the first direction in the absence of user input via the state changer.
[0015] In some embodiments the end effector includes jaws. In some embodiments the actuator movement controller includes a ratchet. In some embodiments the state changer includes a movable trigger. In some embodiments, the controller may further include a state change notifier adapted to provide notice of an impending change in movement controller state that will be caused by further movement of the state changer. In some embodiments, the state changer has a range of motion and the biasing member includes a first spring, the state change notifier includes a second spring. In typical embodiments, the second spring has a spring constant greater than the spring constant of the first spring. The state changer may be disposed with respect to the first and second spring so as to deform the first spring during a first portion of its range of motion in the second state without deforming the second spring and to deform the second spring in a second portion of its range of motion in the second state, the second spring applying a greater force on the state changer in the second portion of its range of motion than the first spring applies on the state changer in the second portion of its range of motion.
[0016] Embodiments of the invention include a method for operating a medical instrument, the instrument including, as summarized above, an end effector at the distal end of a shaft, an end effector actuator at a proximal end of the shaft, and an actuator movement controller. The method includes, without limitation regarding order, (1) actuating the end effector by moving the end effector actuator in a first direction while engaging the actuator movement controller with the end effector actuator to prevent movement of the end effector actuator in a second direction opposite to the first direction, (2) providing a first user input to disengage the actuator movement controller from the end effector actuator to permit movement of the end effector actuator in the first and second directions during the user input, and (3) providing a further user input to disable the actuator movement controller to permit movement of the end effector actuator in the first and second directions in the absence of user input via the state changer.
[0017] In some embodiments, providing the first user input includes moving a trigger. More specifically, moving the trigger may include moving the trigger a first distance and providing the further user input may include moving the trigger to a second distance beyond the first distance.
[0018] The step of providing user input may further include providing notice that further user input will disable the actuator movement controller. In some embodiments, prior to the step of providing a further user input, the method further may include providing notice that further user input will disable the actuator movement controller, and such providing notice may include providing a tactile sensation to the user.
[0019] Providing the first user input may also include moving the trigger a first distance, providing the further user input may include moving the trigger to a second distance beyond the first distance, the step of providing notice comprising providing increased resistance to trigger movement after moving the trigger the first distance but prior to moving the trigger the second distance.
[0020] Before providing the further user input, the method further may include removing the first user input to re-engage the actuator movement controller with the end effector actuator to prevent movement of the end effector actuator in the second direction. Providing the first user input may include moving a trigger and removing the first user input may include releasing the trigger.
[0021] In some embodiments, the method operating a medical instrument may further include providing a subsequent user input after the further user input to re-enable the actuator movement controller. Some embodiments of the method further include ceasing the further uset input prior to providing the subsequent user input. Finally, providing the first user input may include moving the trigger a first distance, providing the further user input may include moving the trigger to a second distance beyond the first distance, ceasing the further user input may include releasing the trigger, and providing the subsequent user input may include moving the trigger.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings which are briefly described below.
[0023] FIG. 1 is a front perspective view of an articulatable surgical tool.
[0024] FIG. 2 is perspective view of a surgical tool in an articulated position.
[0025] FIG. 3 is an exposed side view of a surgical tool with an end effector actuator and an end effector both in an open position.
[0026] FIG. 4 is an exposed side view of a surgical tool with an end effector actuator and an end effector both in a closed position.
[0027] FIG. 5 is a side view of the proximal portion of a tool, showing the handle and proximal end of the shaft, with an articulation locking sleeve in a distal and unlocked position.
[0028] FIG. 6 is a side view of the proximal portion of a tool, showing the handle and proximal end of the shaft, with an articulation locking sleeve in a proximal and locked position.
[0029] FIG. 7 is an exposed view of a portion of a tool from an overhead distal-looking perspective, the portion including the handle, locking rotation knob, and a proximal link.
[0030] FIG. 8 is an exposed view of a handle from a distal-looking perspective.
[0031] FIG. 9 is an exposed view of a handle from a proximal-looking perspective.
[0032] FIG. 10 is an exposed side view of a surgical tool with an end effector actuator and an end effector both in an open position, the end effector jaws embracing an object.
[0033] FIG. 11 is an exposed side view of a surgical tool with an end effector actuator in a closed position and the end effector in an open position, the end effect or jaws embracing an object, the force applied by the closed end effector actuator having been absorbed by a force limiter.
[0034] FIG. 12 is an exposed view of the multi-state ratchet mechanism within the handle, showing from right (distal) to left (proximal), a trigger, toggle, pawl, and rack; in this view, the ratchet is in its enabled and engaged state.
[0035] FIG. 13 is an exposed view of the multi-state ratchet mechanism within the handle as in FIG. 12 ; in this view, the ratchet is in its enabled but disengaged state.
[0036] FIG. 14 is an exposed view of the multi-state ratchet mechanism within the handle as in FIG. 12 ; in this view, the ratchet is still engaged and disabled, but increased resistance provides the user with an indication that further depression of the trigger will change the state of the ratchet from enabled to disabled.
[0037] FIG. 15 is an exposed view of the multi-state ratchet mechanism within the handle as in FIG. 12 ; in this view, the ratchet is in a disabled state.
[0038] FIG. 16 is an exposed view of the multi-state ratchet mechanism within the handle as in FIG. 12 ; in this view, the ratchet is still in a disabled state, but the trigger has been fully released.
[0039] FIG. 17 is an exposed view of the multi-state ratchet mechanism within the handle as in FIG. 12 ; in this view, the ratchet is still in a disabled state with the trigger depressed such that when it is released the ratchet will return to the enabled and engaged state depicted in FIG. 12 .
[0040] FIG. 18 is a simplified side view of the handle showing a trigger; the toggle is located immediately proximal to the trigger (not seen); the position labeled with letters “A” identifies the position of a cross-section detail shown in FIG. 17 .
[0041] FIG. 19 is a cross-sectional detail, as indicated in FIG. 18 , showing the proximal portion of the toggle within a compartment of the handle, with toggle wings in handle slots.
[0042] FIG. 20 is a side view of a toggle in a vertical orientation, the distal- and trigger engaging portion at the top, and the pawl-engaging portion below.
[0043] FIG. 21 is a side view of a trigger from a slightly distal-looking perspective, showing camming surfaces that engage the toggle and stems that engage the handle.
[0044] FIG. 22 shows a trigger (right) and toggle (left) aligned but in an exploded view, exposing a small trigger spring.
[0045] FIG. 23 shows a view of a trigger and toggle with their camming surfaces partially engaged, when the toggle is held in slots of the handle.
[0046] FIG. 24 shows a view of a trigger and toggle with their camming surfaces rotated out of the handle slots such that their camming surfaces are fully engaged.
[0047] FIG. 25 is a perspective view of a pawl.
[0048] FIG. 26 is a side view of a pawl.
DETAILED DESCRIPTION OF THE INVENTION
[0049] Steerable articulating instruments are described in U.S. Pat. No. 7,090,637; US 2005/0107667; US 2005/0273084; US 2005/0273085; and US 2006/0111209, US 2006/0111210. The articulating mechanisms of the tools described in those publications use multiple pairs of segments or links controlled, e.g., by multiple sets of cables. Depending upon the specific design of the device, the links can be discrete segments (as described, e.g., in U.S. Pat. No. 7,090,637) or discrete portions of a flexible segment (as described, e.g., in US 2005/0173085). The instrument may also include steerable or controllable links separated by bushings, e.g., as described in US 2005/0273084 US 2006/0111209 and US 2006/0111210, or any by any other type of link.
[0050] When using such articulating instruments, a user may manipulate the proximal end of the instrument, thereby moving one or more proximal links of the articulation mechanism. This movement results in relative movement of the distal link(s) corresponding to the proximal link(s). It may at times be desirable to lock or otherwise maintain the straight or bent shape of the instrument, as provided by the ability to articulate. In certain embodiments of this invention, the shape of the instrument is maintained by preventing movement of at least one of the proximal links with respect to the rest of the instrument.
[0051] Many instruments, including articulating instruments, have distally-located end effectors (e.g., a set of jaws) that are controlled by proximally-located movable end effector actuators (e.g., a moveable portion of the handle, or a thumbpiece). In typical embodiments of the moveable actuator, movement is possible in two directions, typically opposing or reciprocal. In some embodiments, the end effector actuator has various operation states in which movement is permitted or prevented by a movement controller, such as a ratchet mechanism that has various operating states. The operating states of the end effector actuator are, of course, reflected in the operating state of the end effector.
[0052] Accordingly, certain embodiments of this invention provide methods and devices for changing the operational state of an end effector actuator between a first state (1) in which movement of the actuator is prevented in at least one of two opposite directions; a second state (2) in which the actuator is permitted to move in two directions in response to continuous user input to a state changer; and a third state (3) in which the actuator is permitted to in two directions in the absence of user input to a state changer. Regarding state 1, wherein the ratchet mechanism is engaged, in some embodiments, the movement is disallowed in both directions, in other embodiments, movement is permitted in one direction, and prevented in one. The determinant of whether movement is prevented in one or both directions may be related to the steepness of the angle of mutually engaging teeth of the rack and pawl. The desirability of such variations is associated with the specific use to which the end effector is being applied.
[0053] FIGS. 1-26 show an articulatable tool 100 with an end effector 102 at its distal end and an end effector actuator 104 within a handle 106 at its proximal end. The end effector actuator 104 in typical embodiments of the tool is a movable portion of the handle, typically operated by the thumb of a user, and therefore may be referred to as a thumbpiece. Instrument 100 may be used in various contexts, including medical procedures such as a laparoscopic procedure that requires grasping or cutting within a patient.
[0054] The tool embodiments depicted herein include an ability to articulate, although some embodiments may not articulate. Articulation mechanism components include proximal articulation links 108 and 110 which extend distally from handle 106 , and distal articulation links 112 and 114 extend proximally from end effector 102 . Proximal link 108 is connected to and moves with handle 106 . Likewise, distal link 112 is connected-to and moves with end effector 102 . Further details of ball and socket links suitable for use with this invention may be found in US 2005/0273084, US 2006/0111209, and US 2006/0111210. Embodiments of the presently described invention may make use of any type of link known in the art, the aforementioned specific links are merely offered as examples. An elongated shaft 116 is typically disposed between the proximal links and the distal links. Although the shaft depicted in figures herein is represented as a rigid embodiment, other shaft embodiments may be flexible.
[0055] Further with regard to features that support articulation in the depicted embodiments ( FIGS. 3 and 4 ), a set of tension bearing members 118 is attached to proximal link 108 , extends through proximal link 110 , shaft 116 and distal link 114 and is attached to distal link 112 . (Although not limited to cables, a typical embodiment of a tension bearing member is a cable, and cables will be commonly referred to herein, as exemplary tension bearing members.) A second set of control cables 120 is attached to proximal link 110 , extends through shaft 116 and is attached to distal link 114 . In this embodiment, there are three control cables 118 in the first set and three control cables 120 in the second set. It should be appreciated, however, that other numbers of control cables may be used to connect corresponding proximal and distal links. In addition, mechanisms or tension bearing members other than cables may be used to operably connect corresponding links.
[0056] As shown in FIG. 2 , movement of handle 106 and proximal link 108 with respect to proximal link 110 moves end effector 102 and distal link 112 in a relative and corresponding manner. Likewise, movement of proximal link 110 with respect to shaft link 116 moves distal link 114 with respect to shaft link 116 in a relative and corresponding manner, also as shown in FIG. 2 . This relative articulation movement provides a way for a user to remotely manipulate the end effector through movement of the handle.
[0057] In the shown exemplary embodiments ( FIGS. 1-4 , 10 , and 11 ) the end effector 102 is a pair of jaws. Other end effectors for any surgical or diagnostic application, or for other applications, including non-medical applications, may be used with the articulating tool of this invention. Actuation force is transmitted from end effector actuator 104 through a transmission that includes a linearly movable tension bearing member or rod 125 and a rotatable rod actuator 122 , as shown in FIGS. 3 , 4 , and 7 . In some embodiments, the tension bearing member or rod 125 is also capable of bearing a compressive load, such that an end effector can receive a compressive force transmitted by the end effector actuator.
[0058] In order to maintain a particular position of the end effector with respect to the shaft, whether the position is a straight or neutral position, or an articulated position, the articulating tool of this invention may include an articulation lock. The articulation lock embodiment described below is merely one example, numerous other embodiments are provided in the concurrently filed application of Hegemen et al., entitled “Tool with Articulation Lock”, which is hereby incorporated into this application by this reference.
[0059] In the embodiment shown in FIGS. 1-6 , the articulation lock includes a movable rigid sleeve 130 . In the unlocked position shown in FIGS. 1-5 , sleeve 130 is distal to proximal links 108 and 110 . In the locked position shown in FIG. 6 , however, sleeve 130 has been moved proximally to a position adjacent to and covering links 108 and 110 as well as the proximal end of shaft 116 , thereby blocking relative movement between links 108 and 110 and between link 110 and shaft 116 . In this locked position, relative movement between distal links 112 and 114 and between link 114 and shaft 116 is prevented as well.
[0060] As shown in FIG. 6 , a sleeve support mechanism 132 extends proximally from shaft 116 to provide sliding support for sleeve 130 . A distal stop 134 provides a limit of distal movement of sleeve 130 ; a similar stop (not shown) is provided on or within handle 106 to limit proximal movement of sleeve 130 . Detents, ridges or other mechanisms may be provided to maintain the sleeve in its proximal or distal positions and to provide tactile feedback to the user regarding the position of the sleeve.
[0061] Some embodiments of the inventive tool with a multi-state ratchet mechanism include features that provide rotatability of end effectors, and some of these embodiments further include a rotation lock that allows or disallows such rotation. A rotation lock may comprise a locking knob 101 , as can be seen in FIGS. 1-7 . Other components of the depicted rotation lock include teeth 103 within the knob 101 that are visible in FIG. 7 ; these teeth engage the complementary teeth 105 within the handle 106 that are visible in FIG. 9 . These embodiments are described in detail in concurrently filed application of Hinman and Danitz entitled “Tool with Rotation Lock”, which is hereby incorporated into this application by this reference.
[0062] Some embodiments of the inventive tool with a multi-state ratchet mechanism include a force limiter that establishes an upper limit on the actuation force that may be delivered to the end effector by the end effector actuator. An embodiment of a force limiter 200 may be seen in FIGS. 3 , 4 , 7 , 10 , and 11 . These embodiments are described in detail in concurrently filed application of Hinman and Bertsch entitled “Tool with End Effector Force Limiter”, which is hereby incorporated into this application by this reference.
[0063] The instrument of this invention has an actuator movement controller, comprising a ratchet mechanism that controls the way that an end effector actuator (a thumbpiece, for example) and an end effector can be moved by a user. A state changer, such as a trigger 224 may be used to change among the end effector actuation states. In the embodiment shown in FIGS. 1-26 , but particularly in FIGS. 12-18 , and as laid out in Table 1, the instrument has three end effector actuation states: (1) a state in which the movement controller is enabled and engaged with the end effector actuator to prevent movement of the end effector actuator in at least one direction—in some embodiments movement is prevented in one direction and permitted in the other while in some embodiments movement in both directions is locked; (2) a state in which the movement controller is enabled and disengaged from the end effector actuator to permit movement of the end effector actuator in a first direction and a second direction opposite to the first direction, the disengagement by virtue of continuous user input via a state changer associated with the movement controller; and (3) a state in which the movement controller is disabled, even without user input via the state changer, to permit movement of the end effector actuator in a first direction and a second direction opposite to the first direction in the absence of user input via the state changer.
[0064] The numbering scheme of these described states (1, 2, and 3) is provided as an aid to understand the invention and its various operational states, and is in merely one of various numbering schemes that could be used. Movement through the states is cyclical, and in some sense, the cycle could be described with any state as a starting point or a “first state”. As will be described further below, movement between states 1 and 2 is “reversible”, and can go in either direction, from state 1 to state 2, and from state 2 to state 1. Movement from state 2 to state 3, however, has a unidirectionality (2 to 3), and is not reversible. Similarly, movement from state 3 (back) to state 1 is not reversible. The “reversibility” of the change between states 1 and 2 provides benefit to the user for the combination of subtlety and precision that it brings to the operation of the tool. Subtlety comes from the intuitiveness of the physical maneuver and for the minimal burden on attention and physical effort that the maneuver requires; precision comes from the on/off nature of the operational impact of the ratcheting lock.
[0000]
TABLE 1
Overview of Operational States of the Movement Controller (Multi-state Ratchet) of One Embodiment
and Associated Aspects
end effector
state changer
toggle
movement controller
state
(jaws) status*
(trigger) status
springs' status
rotation
(ratchet) state
1
jaws movement is
trigger is released
both springs expanded
0°
enabled
engaged
prevented in at least
one direction**
2
jaws can be closed
trigger is partially
light spring compressing
enabled
disengaged
and opened
depressed
“temporarily” or
further trigger
light spring compressed
“reversibly”, i.e., can
depression meets
heavy spring compressing (i.e., state
be re-engaged by
greater resistance
change notifier is providing tactile
trigger release
feedback of imminent change)
3
jaws can be closed
trigger is fully
both springs fully compressed
45°
disabled
disengaged stably
and opened
depressed
trigger is released
both springs expanded
90°
trigger is fully
both springs fully compressed
135°
depressed
back
See State 1, above
see State 1
see State 1
180°
see State 1
see State 1
to 1
*The moveability status of the end effector (i.e., jaws) also applies to the moveability of an end effector actuator, such as a thumbpiece operated by the user.
**The movement prevention may either be one-way (i.e., closing allowed, opening prevented) or two-way (opening and closing both prevented), depending on the nature of the engagement between the ratchet's rack and the pawl.
[0065] Some embodiments provide a movement controller using a ratchet mechanism that, when engaged, permits the end effector actuator to be moved in one direction (e.g., to close a pair of jaws) while preventing the end effector actuator to move in the other direction (to, e.g., maintain the jaws in their closed state). As shown in FIGS. 3 , 4 , 10 , and 11 , for example, the ratchet is formed from a rack of teeth 220 extending from end effector actuator 104 . A movable pawl is rotatably mounted in handle 106 . In other embodiments, the teeth of the rack 220 may be configured with a steepness of angle (not shown) such that the engaged state prevents movement of the pawl with respect to the rack in either direction. In other embodiments, prevention of movement in either direction by the engaged ratchet is provided by other engagement features well known in the art, such as pins or friction surfaces. A user may change the operation state of the ratchet by operating a state changer or trigger 224 which connects to pawl 222 through a toggle 226 .
[0066] Details of the ratchet mechanism and ratchet state changer (e.g., a trigger and a toggle) are shown in FIGS. 12-26 . Toggle-located features and trigger-located features may also be seen more clearly in FIGS. 21 and 22 , respectively. FIGS. 22-24 provide detail on both the trigger 224 and toggle 226 in the context of their mutual alignment and interaction. FIGS. 18 and 19 provide some detail on the state changer (comprising toggle 226 ) and its location within—and interaction with the handle 106 . FIGS. 25 and 26 provide detail on an embodiment of a pawl 222 that is engaged by the toggle 226 . FIGS. 12-18 depict a cycling of an embodiment of a multi-state ratchet or movement controller through its various operational states. These operational states along with the status of various of its components are also shown in Table 1.
[0067] In FIG. 12 , the ratchet is in its enabled and engaged state, with the trigger fully extended distally, or outwardly from the handle. In this state, there is little or no actuation force being applied to trigger 224 by a user, and a trigger spring 228 disposed in an internal channel 225 formed in trigger 224 (only visible in cut-away portion of FIG. 16 ) biases trigger 224 distally away from a distal extension 229 of toggle 226 . In some embodiments, the dimensions of the trigger 224 and toggle 226 are such that in this state an optional gap occurs in channel 225 (not shown) between trigger 224 and toggle 226 simply for the purpose of reducing occurrence of the trigger vibrating in response to movements of the pawl.
[0068] Toggle 226 has a pair of wings 230 . In the enabled and engaged state, shown in FIG. 12 , wings 230 are disposed in a pair of corresponding slots 232 formed in handle 106 . (A cross-section of the toggle and handle in this state is shown in FIG. 19 .) The proximal end 227 of toggle 226 engages pawl 222 .
[0069] As shown in FIG. 13 , the ratchet is still enabled, but it has become temporarily or reversibly disengaged by the trigger being partially depressed, per the second of three states as described above. As the trigger 224 is depressed and moved proximally by a user, trigger 224 engages toggle 226 , and both elements move proximally against the operation or bias of a first toggle spring 234 . A pair of stems 236 extend laterally and about midway from trigger 224 , and ride in corresponding channels 240 formed in handle 106 (see FIGS. 8 and 9 ) to guide the linear motion and to prevent rotation of trigger 224 . In the position shown in FIG. 13 , the ratchet is in the enabled-but-disengaged state in which the user may freely move end effector actuator in both directions so long as the user continues to hold the trigger 224 depressed. The toggle's wings 230 are still in their handle slots 232 , and if the user releases trigger 224 , the toggle (and trigger) will move distally under the operation of spring 234 to re-engage the ratchet and return to the enabled and engaged state shown in FIG. 12 .
[0070] By way of reviewing the operational status of the ratchet mechanism in this second state, several aspects are notable. The ratchet is temporarily disengaged by virtue of the teeth of the rack and the teeth of the pawl not being engaged. The disengagement is maintained as long as the user provides an input force that maintains the trigger in a partially depressed position. The disengagement is temporary (or provisional or reversible) inasmuch as the user can release the trigger to its biased outward position, whereupon the ratchet returns to its first state, as described above, of being engaged. Finally, the releasing and partially depressing of the trigger to go back and forth between the first state ( FIG. 12 ) and second state ( FIG. 13 ) is repeatable.
[0071] In FIG. 13 , a second toggle spring 246 biases a ring 244 distally against a shoulder 248 formed in handle 106 . If instead of releasing the trigger, the user continues to push trigger 224 proximally from the position shown in FIG. 13 , a proximally-facing shoulder 242 on toggle 226 engages ring 244 and moves it against the bias provided by spring 246 . In this embodiment, spring 246 is stiffer (i.e., it has a greater spring constant) than spring 234 ; the user will therefore receive tactile feedback in the form of increased resistance to further trigger pushing as soon as toggle shoulder 242 pushes ring 244 proximally, as shown in FIG. 14 .
[0072] While the ratchet state in FIG. 14 is still enabled but disengaged (the second state as described above) the increased resistance provides the user with an indication that depressing the trigger further will change the state of the ratchet from enabled to disabled, as further described below. The ratchet mechanism in FIG. 14 , by being in the second state (enabled and disengaged, as in FIG. 13 ), will still return to the first state (enabled and engaged) upon release of the trigger to its biased distal position. The new aspects of the state depicted in FIG. 14 (vs. FIG. 13 ) involve the trigger being yet further depressed, and the greater resistance thereby encountered by the user, which is perceived as a tactile feedback. The greater resistance is a manifestation of a state change notice provided by the state change notifier comprising spring 246 . In this embodiment, the information provided by the state change notice is that the mechanism is nearly ready to move into a disabled state (the third state, as described above), wherein the ratchet is stably disengaged, and unable to passively revert to the first state.
[0073] FIGS. 15 and 16 depict the ratchet mechanism at different points in the third state, wherein the ratchet is disabled, and ultimately stably disengaged. FIG. 15 shows the toggle transitioning to the stably disengaged state as shown in FIG. 16 . In FIG. 15 , toggle 226 has been pulled proximally sufficiently to enable wings 230 to leave slots 232 . Trigger 224 has four identical helical camming surfaces 250 on its proximal end which engage with four corresponding camming surfaces on the distal end of toggle 226 . The four camming surfaces are of two kinds, though identical in slope: two camming surfaces 252 on wings 230 , and two camming surfaces 254 on the enlarged shaft portion of toggle 226 . Camming surfaces of the toggle 226 and trigger 224 are most easily seen in FIGS. 20 and 21 , respectively. In the enabled and engaged state, shown in FIG. 12 , and the enabled and disengaged state, shown in FIGS. 13 and 14 , the longitudinal shoulder 256 or 257 at the end of each toggle camming surface is offset from the longitudinal shoulders 258 at the end of each trigger camming surface. Once wings 230 leave slots 232 , however, toggle 226 is free to rotate under the camming interaction of surfaces 250 against surfaces 252 and 254 . Toggle 226 will rotate 45° until the toggle longitudinal surfaces 256 and 257 meet the trigger longitudinal surfaces 258 , as shown in FIG. 15 .
[0074] When the user releases trigger 224 from the position shown in FIG. 15 , the toggle and trigger move distally together until camming surfaces 252 on toggle 226 engage two camming surfaces 260 formed on the inside of handle 106 (seen best in FIGS. 8 and 9 ) that cause the toggle to rotate another 45° (to reach a point of 90° rotation from the reference point of the first state) until longitudinal surfaces 257 meet corresponding handle longitudinal surfaces 262 . The handle camming surfaces hold toggle 226 and prevent further distal movement from this position; trigger 224 continues to move distally under the action of spring 228 , as shown in FIG. 16 . In this state, the ratchet is disengaged, the trigger 224 is fully released and distal, and the user may freely move end effector actuator 104 (and consequently the end effector or jaws 102 ) in either direction.
[0075] To return the ratchet to the enabled states, the user depresses trigger 224 again to move trigger camming surfaces 250 against toggle camming surfaces 252 and 254 . When proximal movement of trigger 224 moves toggle 226 sufficiently proximal for the toggle's longitudinal surfaces 257 to clear the handle longitudinal surfaces 262 , the camming action between the trigger and toggle once again rotates the toggle 45° to the state shown in FIG. 17 . When the user releases trigger 224 , engagement of toggle camming surfaces 252 with two other camming surfaces 264 formed in handle 106 causes another 45° rotation of toggle 226 until wings 230 reach slots 232 , thereby enabling toggle 226 to move distally under the action of spring 234 to the enabled and engaged ratchet state shown in FIG. 12 . At this point, the toggle has rotated 180° from its reference position of the initial first state. Two cycles of moving through the first to third state take the toggle through a complete 360° rotation.
[0076] While the inventive surgical instruments and devices have been described in some detail by way of illustration, such illustration is for purposes of clarity of understanding only. It will be readily apparent to those of ordinary skill and in the art in light of the teachings herein that certain changes and modifications may be made thereto without departing from the spirit and scope of the appended claims. For example, while the multi-state ratchet mechanism described in here has typically been in the context of tools with an articulating mechanism comprising at least two links, the mechanisms may be used in an instrument comprising only a single link, a multiplicity of links, and with any number of cables or cable sets operably connecting the links. Further, while the context of the invention is considered to be surgical or medical diagnostic procedures, embodiments of the multi-sate ratchet mechanism or tools having such a mechanism may have utility in other non-medical contexts as well.
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The invention provides surgical or diagnostic tools and associated methods that offer improved user control for operating remotely within regions of the body. These tools include a proximally-located actuator for the operation of a distal end effector, as well as proximally-located actuators for articulational and rotational movements of the end effector. Control mechanisms and methods refine operator control of end effector actuation and of these articulational and rotational movements. A multi-state ratchet for end effector actuation provides enablement-disablement options with tactile feedback. The tool may also include other features. A force limiter mechanism protects the end effector and manipulated objects from the harm of potentially excessive force applied by the operator. An articulation lock allows the fixing and releasing of both neutral and articulated configurations of the tool and of consequent placement of the end effector. A rotation lock provides for enablement and disablement of rotatability of the end effector.
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CROSS REFERENCES TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. Ser. No. 11/217,039 filed Aug. 31, 2005, entitled “Modified Landplaster as a Wallboard Filler,” herein incorporated by reference.
This application is related to co-pending U.S. Ser. No. 11/152,317, entitled “Modifiers for Gypsum Slurries and Method of Using Them”, U.S. Ser. No. 11/152,418 entitled “Gypsum Products Utilizing a Two-Repeating Unit System and Process for Making Them”, and U.S. Ser. No. 11/152,661, entitled “Fast Drying Gypsum Products”, all filed Jun. 14, 2005, and herein incorporated by reference.
This application is further related to co-pending U.S. Ser. No. 11/450,068, entitled “Modifiers for Gypsum Slurries and Method of Using Them”, and U.S. Ser. No. 11/449,924, entitled “Gypsum Products Utilizing a Two-Repeating Unit System and Process for Making Them”, both filed Jun. 9, 2006 and herein incorporated by reference.
FIELD OF THE INVENTION
The present invention is directed to a composition utilizing a coated landplaster as a filler in gypsum slurries. More specifically, landplaster is coated with a coating that is less soluble than stucco to reduce or delay its ability to catalyze crystallization reactions.
BACKGROUND OF THE INVENTION
Gypsum-based building products are commonly used in construction. Wallboard made of gypsum is fire retardant and can be used in the construction of walls of almost any shape. It is used primarily as an interior wall and ceiling product. Gypsum has sound-deadening properties. It is relatively easily patched or replaced if it becomes damaged. There are a variety of decorative finishes that can be applied to the wallboard, including paint and wallpaper. Even with all of these advantages, it is still a relatively inexpensive building material.
Gypsum is also known as calcium sulfate dihydrate, terra alba or landplaster. Plaster of Paris is also known as calcined gypsum, stucco, calcium sulfate semihydrate, calcium sulfate half-hydrate or calcium sulfate hemihydrate. Synthetic gypsum, for example, that which is a byproduct of flue gas desulfurization processes from power plants, may also be used. When it is mined, raw gypsum is generally found in the dihydrate form. In this form, there are two water molecules associated with each molecule of calcium sulfate. To produce the hemihydrate form, the gypsum is calcined to drive off some of the water of hydration by the following equation:
CaSO 4 .2H 2 O→CaSO 4 →½H 2 O+ 3/2H 2 O
A number of useful gypsum products can be made by mixing the stucco with water and permitting it to set by allowing the calcium sulfate hemihydrate to react with water to convert the hemihydrate into a matrix of interlocking calcium sulfate dihydrate crystals. As the matrix forms, the product slurry becomes firm and holds a desired shape. Excess water must then be removed from the product by drying.
Significant amounts of energy are expended in the process of making gypsum articles. Landplaster is calcined to make stucco by heating it to drive off water of hydration. Later the water is replaced as the gypsum sets by hydration of the hemihydrate to the dihydrate form. Excess water used to fluidize the slurry is then driven from the set article by drying it in an oven or a kiln. Thus, reducing the amount of water needed to fluidize the slurry turns into a monetary savings when fuel requirements are decreased. Additional fuel savings would result if the amount of material that required calcining were reduced.
Attempts have been made to reduce the amount of water used to make a fluid slurry using dispersants. Polycarboxylate superplasticizers are very effective in allowing water reduction and where water reduction results in increased density, a strength increase is achieved. These materials are relatively expensive. When used in large doses, polycarboxylate dispersants can be one of the single, most expensive additives in making gypsum products. The high price of this component can overcome the narrow margins afforded these products in a highly competitive marketplace.
Another disadvantage associated with polycarboxylate dispersants is the retardation of the setting reaction. Gypsum board is made on high speed production lines where the slurry is mixed, poured, shaped and dried in a matter of minutes. The board must be able to hold its shape to be moved from one conveyor line to another to put the board into the kiln. Damage can occur if the boards have not attained a minimum green strength by the time they are cut to length and handled during the manufacturing process. If the board line has to be slowed down because the board is not sufficiently set to move on to the next step in the process, production costs are driven up, resulting in an economically uncompetitive product.
Modifiers have been found that increase the efficacy of the dispersant in fluidizing the slurry, allowing the modifier to replace a portion of the expensive dispersant while still reducing water demand. However, it has been found that the modifier does not work consistently, depending on how and when it is added to the slurry. Thus, there is a need for a delivery vehicle to carry the modifier to the slurry in a manner that allows it to perform consistently so that the amount of dispersant can be reduced.
The use of fillers that are easily fluidizable in water have been considered as another method of reducing fuel demand. However, one of the important properties of gypsum products, and especially gypsum panels or wallboard, is its fire resistance. Calcium sulfate dihydrate is approximately 20% water by weight. Replacing a portion of the calcined gypsum with fillers that are less fire retardant diminishes this property in the finished product. Many fillers also reduce the compressive strength and the nail pull strength of wallboard.
Landplaster has been used as a filler in gypsum products. It is also fire retardant, inexpensive, readily available and reduces the amount of calcined gypsum that is needed, but it also has disadvantages. Calcium sulfate dihydrate used in sufficient quantities to act as a filler also acts as a set accelerator for the hemihydrate by providing seed crystals that start the crystallization process more quickly. This leads to premature stiffening of the slurry.
Thus there is a need in the art for a filler for use in gypsum articles, particularly wallboard, that reduces fuel consumption by replacing calcined gypsum, by reducing the amount of water driven from the set product or both. The filler should have fire retardancy approximately equal to set gypsum and it should be inexpensive, readily available and should not decrease the strength of the finished product.
The prior art has failed to adequately address the problem of improving the efficacy of a given polycarboxylate dispersant. Improving the efficacy of a dispersant would reduce the cost of the dispersant and maintaining the reasonable price of gypsum products.
Thus, there is a need in the art to reduce the dosage of dispersants used in a gypsum slurry while maintaining flowability of the slurry. Reduction in dispersant use would result in saving of costs spent on the dispersant and would reduce adverse side effects, such as set retardation.
SUMMARY OF THE INVENTION
These and other needs are met or exceeded by the use of the present invention which utilizes an improved, coated landplaster as a filler in gypsum products. The coated landplaster also optionally serves as a delivery vehicle for a modifier that enhances performance of polycarboxylate dispersants.
One embodiment of this invention is drawn to a gypsum slurry that includes calcium sulfate hemihydrate, water and calcium sulfate dihydrate coated with a hydrophilic, dispersible coating. The coating is less soluble than the calcium sulfate dihydrate to delay exposure of the landplaster to the remainder of the slurry, preventing premature crystallization and the early stiffening that accompanies it.
Another embodiment of this invention is a gypsum slurry that includes calcium sulfate hemihydrate, a polycarboxylate dispersant, water and coated calcium sulfate dihydrate. In this case, the hydrophilic, dispersible coating is selected to serve as a modifier to enhance the ability of the dispersant to fluidize the gypsum slurry.
A method of making the slurry includes selecting a coating that is less soluble than calcium sulfate hemihydrate. Calcium sulfate dihydrate is coated with the hydrophilic, dispersible coating, then combined with water and calcium sulfate hemihydrate.
Replacement of a portion of the calcined gypsum with coated landplaster results in lower requirements for calcined gypsum, resulting in savings realized from a reduction in fuel and power consumed by the calcining process. Plants that are limited by stucco production may also achieve an increase in capacity since more wallboard can be made with the same amount of stucco.
Coating of the landplaster reduces its ability to act as a set accelerator. By covering the landplaster crystal, the hemihydrate molecules do not have access to the seed crystals as long as the coating remains in place. As the coating dissolves into the slurry water, the landplaster is exposed and begins to catalyze the hydration reactions. However, removal of the coating takes time that delays initiation of the setting reactions so that premature stiffening of the slurry is minimized or avoided. Another possibility it that the coating is insoluble and merely renders the landplaster inert. The ability to control when the landplaster is available to initiate setting reactions allows reduction the usage of set accelerator, resulting in a cost savings.
If the coating is highly dispersible, the landplaster may disperse in the slurry more easily than the calcined gypsum it replaces, allowing a further reduction in the water needed to fluidize the slurry. Less fuel will be required for the kiln where there is less water to dry from the product. Instead of the energy savings, plants that are kiln-limited can realize additional capacity from increased line speeds and sale of additional product.
Where there is a capacity increase, it is obtained without a significant increase in capital spending. This capital becomes available for other projects or interest that may have been paid could be saved. Since a large number of plants are limited by either stucco production or by kiln drying, use of this coating could have wide application.
In some embodiments, the loss in strength is avoided entirely. Landplaster results in higher strengths than many other fillers. At least one of the preferred coatings results in a product where there is no loss in strength at all. This produces a particularly good product, having many of the properties of gypsum set from 100% calcined gypsum.
When used in formulations with polycarboxylate dispersants, the coated landplaster is also usable as a vehicle to deliver a modifier for enhancement of the dispersant. A number of modifiers are known and are suitable for deposition onto the landplaster particle.
DETAILED DESCRIPTION OF THE INVENTION
The gypsum slurry of this invention is made using water, calcined gypsum and a coated landplaster. Although the benefits of this invention are most clear when used in a slurry that includes a polycarboxylate, it is useful in any embodiment where it is desirable to utilize landplaster as a filler but premature thickening is to be avoided.
Any calcined gypsum or stucco is useful in this slurry. Either alpha or beta calcined stucco is useful. Stuccos from a variety of sources can be used, including synthetic gypsum. As discussed below, average or low salt stuccos are preferred in embodiments where polycarboxylate dispersants are used due to possible interaction.
Landplaster is used as a filler to replace a portion of the stucco. Since landplaster is already in the dihydrate form, it requires no water of hydration and thus has less of a water demand than stucco. However, landplaster does not participate in the crystal formation reactions, and therefore does not become bound into the crystal matrix to the same degree as the hemihydrate. Some loss in strength occurs, particularly if the amount of landplaster exceeds 10% of the total amount of gypsum materials. Any amount of landplaster may be used, but preferably, the amount of landplaster is about 3-10% of the total calcium sulfate materials on a dry basis. As used in this application, the term “calcium sulfate materials” includes calcium sulfate in all of its forms, including the anhydrate, hemihydrate and the dihydrate forms.
The landplaster is coated with any applicable coating that prevents early onset of thickening of the gypsum slurry. Preferably, the coating is less soluble than the stucco, providing time for mixing and incorporation of other additives before the landplaster is exposed. The coating is applicable to the landplaster in any suitable coating method. Preferably the landplaster is added to a coating solution. Once coated, the landplaster is optionally dried for later use. However, in a preferred coating method, the coating is precipitated onto the landplaster while the landplaster remains slurried with the coating solution. Energy required to dry the landplaster is saved. The coating slurry with the coated landplaster is then incorporated with the stucco slurry before the product is formed. Coated landplaster, water, excess coating and/or byproducts are all added to the stucco slurry prior to final mixing.
Many coatings are useful in the present invention. Preferred coatings include DEQUEST particularly DEQUEST 2006, phosphonate dispersants (Solutia, St. Louis, Mo.) or calcium carbonate. Other coatings made of trisodium phosphate or tetrasodium pyrophosphate are also useful. Any material is usable that is capable of being coated onto the landplaster particles, that is less soluble than the landplaster and reduces the active sites of nucleation.
The coating that is particularly useful is calcium carbonate. The coating is preferably formed by precipitation of the calcium carbonate onto the calcium sulfate dihydrate, or landplaster, from solution. One embodiment of the coating is obtained by combining hydrated lime, such as calcium magnesium hydroxide, and soda ash or sodium carbonate. Next the calcium sulfate dihydrate is added. A replacement reaction occurs, bringing calcium carbonate together to form a solid. The addition of lime also causes the calcium carbonate to precipitate onto the landplaster specifically, rather than on the interior of the mixer or other equipment. After the coated landplaster has been prepared, the stucco and any other additives are added to the slurry. When 10% by weight of the total calcium sulfate material is in the form of landplaster coated with calcium carbonate and 90% by weight of the calcium sulfate material is in the form of hemihydrate, almost 10% water reduction is achieved compared to 100% hemihydrate.
Preferably, the water is warm when the lime and soda ash are added to it. Use of warm water appears to improve the efficacy of the coating process. Water temperatures up to 120° F. are especially useful for dissolving the salts, and the use of higher temperatures is contemplated.
In some embodiments, reduction in the amount of water used to make the slurry is achieved by the addition of a dispersant, such as a polycarboxylate or naphthalene sulfonate. The dispersant attaches itself to the calcium sulfate, then charged groups on the backbone and the side chains on the branches of the polymer repel each other, causing the gypsum particles to spread out and flow easily. When the slurry flows more easily, the amount of water can be reduced and still obtain a flowable fluid. In general, reduction in water results in lower drying costs.
Any polycarboxylate dispersant that is useful for improving fluidity in gypsum is preferred in the slurry of this invention. A number of polycarboxylate dispersants, particularly polycarboxylic ethers, are preferred types of dispersants. One of the preferred class of dispersants used in the slurry includes two repeating units. It is described further in co-pending U.S. Ser. No. 11/152,418, entitled “Gypsum Products Utilizing a Two-Repeating Unit System and Process for Making Them”, previously incorporated by reference. These dispersants are products of Degussa Construction Polymers, GmbH (Trostberg Germany) and are supplied by Degussa Corp. (Kennesaw, Ga.) (hereafter “Degussa”) and are hereafter referenced as the “PCE211-Type Dispersants”.
The first repeating unit is an olefinic unsaturated mono-carboxylic acid repeating unit, an ester or salt thereof, or an olefinic unsaturated sulphuric acid repeating unit or a salt thereof. Preferred first repeating units include acrylic acid or methacrylic acid. Mono- or divalent salts are suitable in place of the hydrogen of the acid group. The hydrogen can also be replaced by hydrocarbon group to form the ester.
The second repeating unit satisfies Formula I,
and R 1 is derived from an unsaturated (poly)alkylene glycol ether group according to Formula II.
Referring to Formula I, the alkenyl repeating unit optionally includes a C 1 to C 3 alkyl group between the polymer backbone and the ether linkage. The value of p is an integer from 0-3, inclusive. Preferably, p is either 0 or 1. R 2 is either a hydrogen atom or an aliphatic C 1 to C 5 hydrocarbon group, which may be linear, branched, saturated or unsaturated. Examples of preferred repeating units include acrylic acid and methacrylic acid.
The polyether group of Formula II contains multiple C 2 -C 4 alkyl groups, including at least two different alkyl groups, connected by oxygen atoms. M and n are, independently, integers from 2 to 4, inclusive. Preferably, at least one of m and n is 2. X and y are, independently, integers from 55 to 350, inclusive. The value of z is from 0 to 200, inclusive. R 3 is a non-substituted or substituted aryl group and preferably phenyl. R 4 is hydrogen or an aliphatic C 1 to C 20 hydrocarbon group, a cycloaliphatic C 5 to C 8 hydrocarbon group, a substituted C 6 to C 14 aryl group or a group conforming at least one of Formula III(a), III(b) and III(c).
In the above formulas, R 5 and R 7 , independently of each other, represent an alkyl, aryl, aralkyl or alkylaryl group. R 6 is a bivalent alkyl, aryl, aralkyl or alkylaryl group. A particularly useful dispersant of the PCE211-Type Dispersants is designated PCE211 (hereafter “211”). Other polymers in this series known to be useful in wallboard include PCE111. PCE211-Type dispersants are described more fully in U.S. Ser. No. 11/152,678, filed Jun. 14, 2005, and a continuation-in-part of U.S. Ser. No. 11/152,678, filed June, 2006 by Degussa Construction Polymers, both entitled “Polyether-Containing Copolymer”, and herein incorporated by reference.
The molecular weight of the PCE211 Type dispersant is preferably from about 20,000 to about 60,000 Daltons. Surprisingly, it has been found that the higher molecular weight dispersants cause less retardation of set time than dispersants having a molecular weight greater than 60,000 Daltons. Generally longer side chain length, which results in an increase in overall molecular weight, provides better dispersibility. However, tests with gypsum indicate that efficacy of the dispersant is reduced at molecular weights above 50,000 Daltons.
The first repeating unit preferably makes up from about 30% to about 99 mole % of the total repeating units, more preferably from about 40 to about 80%. From about 1 to about 70 mole % of the repeating units are the second repeating unit, more preferably from about 10 to about 60 mole %.
Another class of polycarboxylate compounds that are useful in this invention is disclosed in U.S. Pat. No. 6,777,517, herein incorporated by reference and hereafter referenced as the “2641-Type Dispersant”. Preferably, the dispersant includes at least three repeating units shown in Formula IV(a), IV(b) and IV(c).
In this case, both acrylic and maleic acid repeating units are present, yielding a higher ratio of acid groups to vinyl ether groups. R 1 represents a hydrogen atom or an aliphatic hydrocarbon radical having from 1 to 20 carbon atoms. X represents OM, where M is a hydrogen atom, a monovalent metal cation, an ammonium ion or an organic amine radical. R 2 can be hydrogen, an aliphatic hydrocarbon radical having from 1 to 20 carbon atoms, a cycloaliphatic hydrocarbon radical having from 6 to 14 carbon atoms, which may be substituted. R 3 is hydrogen or an aliphatic hydrocarbon radical having from 1 to 5 carbon atoms, which are optionally linear or branched, saturated or unsaturated. R 4 is hydrogen or a methyl group, depending on whether the structural units are acrylic or methacrylic. P can be from 0 to 3. M is an integer from 2 to 4, inclusive, and n is an integer from 0 to 200, inclusive. PCE211-Type and 2641-Type dispersants are manufactured by Degussa Construction Polymers, GmbH (Tröstberg, Germany) and marketed in the United States by Degussa Corp. (Kennesaw, Ga.). Preferred 2641-Type Dispersants are sold by Degussa as MELFLUX 2641F, MELFLUX 2651F and MELFLUX 2500L dispersants. 2641-Type dispersants (MELFLUX is a registered trademark of Degussa Construction Polymers, GmbH) are described for use in wallboard and gypsum slurries in U.S. Ser. No. 11/152,661, entitled “Fast Drying Wallboard”, previously incorporated by reference.
Yet another preferred dispersant family is sold by Degussa and referenced as “1641-Type Dispersants”. This dispersant is more fully described in U.S. Pat. No. 5,798,425, herein incorporated by reference. A particularly preferred 1641-Type Dispersant is shown in Formula VI and marketed as MELFLUX 1641F dispersant by Degussa. This dispersant is made primarily of two repeating units, one a vinyl ether and the other a vinyl ester. In Formula V, m and n are the mole ratios of the component repeating units, which can be randomly positioned along the polymer chain.
These dispersants are particularly well-suited for use with gypsum. While not wishing to be bound by theory, it is believed that the acid repeating units bind to the hemihydrate crystals while the long polyether chains of the second repeating unit perform the dispersing function. Since it is less retardive than other dispersants, it is less disruptive to the manufacturing process of gypsum products such as wallboard. The dispersant is used in any effective amount. To a large extent, the amount of dispersant selected is dependant on the desired fluidity of the slurry. As the amount of water decreases, more dispersant is required to maintain a constant slurry fluidity. Since polycarboxylate dispersants are relatively expensive components, it is preferred to use a small dose, preferably less than 2% or more preferably less than 1% by weight based on the weight of the dry calcium sulfate material. Preferably, the dispersant is used in amounts of about 0.05% to about 0.5% based on the dry weight of the calcium sulfate material. More preferably, the dispersant is used in amounts of about 0.01% to about 0.2% on the same basis. In measuring a liquid dispersant, only the polymer solids are considered in calculating the dosage of the dispersant, and the water from the dispersant is considered when a water/stucco ratio is calculated.
Many polymers can be made with the same repeating units using different distributions of them. The ratio of the acid-containing repeating units to the polyether-containing repeating unit is directly related to the charge density. Preferably, the charge density of the co-polymer is in the range of about 300 to about 3000 μequiv. charges/g co-polymer. It has been found that the most effective dispersant tested for water reduction in this class of dispersants, MELFLUX 2651F, has the highest charge density.
However, it has also been discovered that the increase in charge density further results in an increase in the retardive effect of the dispersant. Dispersants with a low charge density, such as MELFLUX 2500L, retard the set times less than the MELFLUX 2651F dispersant that has a high charge density. Since retardation in set times increases with the increase in efficacy obtained with dispersants of high charge density, making a slurry with low water, good flowability and reasonable set times requires keeping of the charge density in a mid-range. More preferably, the charge density of the co-polymer is in the range of about 600 to about 2000 μequiv. charges/g co-polymer.
Modifiers are optionally added to a gypsum slurry to enhance performance of a polycarboxylate dispersant. The modifier can be any substance, liquid or solid, which when combined with a polycarboxylate dispersant in a gypsum slurry, leads to an improvement the efficacy of the dispersant. Modifiers are not intended to be dispersants in themselves, but serve to allow the dispersant to be more effective. For example, at constant concentrations of dispersant, better fluidity is obtained when the modifier is used compared to the same slurry without the modifier.
Although the exact chemistry involved in the use of modifiers is not fully understood, at least two different mechanisms are responsible for the increase in dispersant efficacy. Lime, for example, reacts with the polycarboxylate in the aqueous solution to uncoil the dispersant molecule. In contrast, soda ash reacts on the gypsum surface to help improve the dispersant effect. Any mechanism can be used by the modifier to improve the efficacy of the dispersant for the purposes of this invention. Theoretically, if the two mechanisms work independently, combinations of modifiers can be found that utilize the full effect of both mechanisms and result in even better dispersant efficacy.
Preferred modifiers include cement, lime, also known as quicklime or calcium oxide, slaked lime, also known as calcium hydroxide, soda ash, also known as sodium carbonate, potassium carbonate, also known as potash, and other carbonates, silicates, hydroxides, phosphonates and phosphates. Preferred carbonates include sodium and potassium carbonate. Sodium silicate is a preferred silicate.
When lime or slaked lime is used as the modifier, it is used in concentrations of about 0.15% to about 1.0% based on the weight of the dry calcium sulfate material. In the presence of water, lime is quickly converted to calcium hydroxide, or slaked lime, and the pH of the slurry becomes alkaline. The sharp rise in pH can cause a number of changes in the slurry chemistry. Certain additives, including trimetaphosphate, break down as the pH increases. There can also be problems with hydration and, where the slurry is used to make wallboard or gypsum panels, there are problems with paper bond at high pH. For workers who come in contact with the slurry, strongly alkaline compositions can be irritating to the skin and contact should be avoided. Above pH of about 11.5, lime no longer causes an increase in fluidity. Therefore, it is preferred in some applications to hold the pH below about nine for maximum performance from this modifier. In other applications, such as flooring, a high pH has the benefit of minimizing mold and mildew. Alkali metal hydroxides, especially sodium and potassium hydroxides are preferred for use in flooring.
Other preferred modifiers include carbonates, phosphonates, phosphates and silicates. Preferably, the modifiers are used in amounts less than 0.25% based on the weight of the dry calcium sulfate material. Above these concentrations, increases in the amount of modifier causes a decrease in the dispersant efficacy. These modifiers are preferably used in amounts of from about 0.05 to about 0.2 weight %.
Many of the modifiers disclosed above are advantageously applied as the landplaster coating. In such cases, the coated landplaster serves two functions, that of reducing premature thickening of the slurry, as well as a delivery vehicle for the modifier. Water demand of the slurry is reduced by permitting use of a dihydrate filler, as well as delivering the modifier that enhances the efficacy of the dispersant. The resulting slurry utilizes water very efficiently.
The charge density of the dispersant has also been found to affect the ability of the modifier to interact with the dispersant. Given a family of dispersants with the same repeating units, the modifier causes a greater increase in efficacy in the dispersant having the higher charge density. It is important to note that although the general trend is to obtain a higher efficacy boost with higher charge density, when comparing the effectiveness of dispersants having different repeating units, the effectiveness of the dispersants may be considerably different at the same charge density. Thus, adjustment of the charge density may not be able to overcome poor fluidity with a particular family of dispersants for that application.
It has also been noted that the reaction of the polycarboxylate dispersants and the modifiers react differently when used in different gypsum media. While not wishing to be bound by theory, the impurities present in gypsum are believed to contribute to the efficacy of both the dispersant and the modifier. Among the impurities present in stucco are salts that vary by geographical location. Many salts are known to be set accelerators or set retarders. These same salts may also change the efficacy of the polycarboxylate dispersant by affecting the degree of fluidity that can be achieved. Some preferred polycarboxylates, including the PCE211-Type Dispersants, are best utilized with a low salt stucco. Other dispersants, such as the 2641-Type Dispersants are suitable for use with high-salt stuccos.
As a result of the use of fluidity enhancing dispersants and modifiers to boost their performance, the amount of water used to fluidize the slurry can be reduced compared to slurries made without these additives. It must be understood that the stucco source, the calcining technique, the dispersant family, the charge density and the modifier all work together to produce a slurry of a given fluidity. In the laboratory, it is possible to reduce the water level close to, equal to, or even below that theoretically required to fully hydrate the calcium sulfate hemihydrate. When used in a commercial setting, process considerations may not allow water reduction to this degree.
When used to make gypsum board, a number of additives are useful to improve the properties of the finished article. Traditional amounts of additives are used. Amounts of several additives are reported as “lbs/MSF,” which stands for pounds of additive per one thousand square feet of board.
Some embodiments of the invention employ a foaming agent to yield voids in the set gypsum-containing product to provide lighter weight. In these embodiments, any of the conventional foaming agents known to be useful in preparing foamed set gypsum products can be employed. Many such foaming agents are well known and readily available commercially, e.g. the HYONIC line of soaps from GEO Specialty Chemicals, Ambler, Pa. Foams and a preferred method for preparing foamed gypsum products are disclosed in U.S. Pat. No. 5,683,635, herein incorporated by reference.
Dispersants are used to improve the flowability of the slurry and reduce the amount of water used to make the slurry. Any known dispersant is useful, including polycarboxylates, sulfonated melamines or naphthalene sulfonate. Naphthalene sulfonate is another preferred dispersant, and is used in amounts of about 0 lb/MSF to 18 lb/MSF (78.5 g/m 2 ), preferably from about 4 lb/MSF (17.5 g/m 2 ) to about 12 lb/MSF (52.4 g/m 2 ). A preferred naphthalene sulfonate dispersant is DAXAD Dispersant (Dow Chemical, Midland, Mich.). Even where dispersants are used in the coating, it maybe advantageous to have additional dispersant to further improve the fluidity of the slurry.
A trimetaphosphate compound is added to the gypsum slurry in some embodiments to enhance the strength of the product and to improve sag resistance of the set gypsum. Preferably the concentration of the trimetaphosphate compound is from about 0.07% to about 2.0% based on the weight of the calcium sulfate material. Gypsum compositions including trimetaphosphate compounds are disclosed in U.S. Pat. Nos. 6,342,284 and 6,632,550, both herein incorporated by reference. Exemplary trimetaphosphate salts include sodium, potassium or lithium salts of trimetaphosphate, such as those available from Astaris, LLC., St. Louis, Mo. Care must be exercised when using trimetaphosphate with lime or other modifiers that raise the pH of the slurry. Above a pH of about 9.5, the trimetaphosphate loses its ability to strengthen the product and the slurry becomes severely retardive.
Other additives are also added to the slurry as are typical for the particular application to which the gypsum slurry will be put. Set retarders (up to about 2 lb./MSF (9.8 g/m2)) or dry accelerators (up to about 35 lb./MSF (170 g/m2)) are added to modify the rate at which the hydration reactions take place. “CSA” is a set accelerator comprising 95% calcium sulfate dihydrate co-ground with 5% sugar and heated to 250° F. (121° C.) to caramelize the sugar. CSA is available from USG Corporation, Southard, Okla. plant, and is made according to U.S. Pat. No. 3,573,947, herein incorporated by reference. Potassium sulfate is another preferred accelerator. HRA is calcium sulfate dihydrate freshly ground with sugar at a ratio of about 5 to 25 pounds (2.2 to 11.4 kg) of sugar per 100 pounds (4.5 kg) of calcium sulfate material. It is further described in U.S. Pat. No. 2,078,199, herein incorporated by reference. Both of these are preferred accelerators.
Another accelerator, known as wet gypsum accelerator or WGA, is also a preferred accelerator. A description of the use of and a method for making wet gypsum accelerator are disclosed in U.S. Pat. No. 6,409,825, herein incorporated by reference. This accelerator includes at least one additive selected from the group consisting of an organic phosphonic compound, a phosphate-containing compound or mixtures thereof. This particular accelerator exhibits substantial longevity and maintains its effectiveness over time such that the wet gypsum accelerator can be made, stored, and even transported over long distances prior to use. The wet gypsum accelerator is used in amounts ranging from about 5 to about 80 pounds per thousand square feet (24.3 to 390 g/m 2 ) of board product.
Other potential additives to the wallboard are biocides to reduce growth of mold, mildew or fungi. Depending on the biocide selected and the intended use for the wallboard, the biocide can be added to the covering, the gypsum core or both. Examples of biocides include boric acid, pyrithione salts and copper salts. Biocides can be added to either the covering or the gypsum core. When used, biocides are used in the coverings in amounts of less than 500 ppm. Pyrithione is known by several names, including 2-mercaptopyridine-N-oxide; 2-pyridinethiol-1-oxide (CAS Registry No. 1121-31-9); 1-hydroxypyridine-2-thione and 1 hydroxy-2(1H)-pyridinethione (CAS Registry No. 1121-30-8). The sodium derivative (C 5 H 4 NOSNa), known as sodium pyrithione (CAS Registry No. 3811-73-2), is one embodiment of this salt that is particularly useful. Pyrithione salts are commercially available from Arch Chemicals, Inc. of Norwalk, Conn., such as Sodium OMADINE or Zinc OMADINE.
In addition, the gypsum composition optionally can include a starch, such as a pregelatinized starch or an acid-modified starch. Starches are used in amounts of from about 3 to about 20 lbs/MSF (14.6 to 97.6 g/m 2 ) to increase paper bond and strengthen product. The inclusion of the pregelatinized starch increases the strength of the set and dried gypsum cast and minimizes or avoids the risk of paper delamination under conditions of increased moisture (e.g., with regard to elevated ratios of water to calcined gypsum). One of ordinary skill in the art will appreciate methods of pregelatinizing raw starch, such as, for example, cooking raw starch in water at temperatures of at least about 185° F. (85° C.) or other methods. Suitable examples of pregelatinized starch include, but are not limited to, PCF 1000 Starch, commercially available from Lauhoff Grain Company and AMERIKOR 818 and HQM PREGEL starches, both commercially available from Archer Daniels Midland Company (Decatur, Ill.). If included, the pregelatinized starch is present in any suitable amount. For example, if included, the pregelatinized starch can be added to the mixture used to form the set gypsum composition such that it is present in an amount of from about 0.5% to about 10% percent by weight of the set gypsum composition. Starches such as USG95 (United States Gypsum Company, Chicago, Ill.) are also optionally added for core strength.
Other known additives may be used as needed to modify specific properties of the product. Sugars, such as dextrose, are used to improve the paper bond at the ends of the boards. Wax emulsions or siloxanes are used for water resistance. If stiffness is needed, boric acid is commonly added. Fire retardancy can be improved by the addition of vermiculite. These and other known additives are useful in the present slurry and wallboard formulations. Glass fibers are optionally added to the slurry in amounts of up to 11 lb./MSF (54 g/m 2 ). Up to 15 lb./MSF (73.2 g/m 2 ) of paper fibers are also added to the slurry. Wax emulsions are added to the gypsum slurry in amounts up to 90 lb./MSF (0.439 kg/m 2 ) to improve the water-resistency of the finished gypsum board panel.
Example 1
A number of coatings were added to landplaster and tested in the laboratory for their ability to improve the fluidity of the samples. Components and amounts used in each sample are shown in Table I.
Forty grams of landplaster and water as shown were added to a Hobart Model N-50 mixer followed by addition of the additive. The mixer was turned on low (setting 1) for five minutes. The amount of dispersant was sufficient to yield 0.6 grams of solids. The dispersant was weighed out on a small plastic boat and added to the mixture by hand. Three hundred sixty grams of stucco was then added to the mixer and allowed to soak for 15 seconds. The slurry was mixed on medium speed (setting 2) for 15 seconds.
TABLE I
Patty
Water,
Amt.,
Size,
Stiff
Vicat
Dispersant
grams
Additive
grams
cm
Time
Set
211
200
Control
0.0
22.8
2:55
9:00
211
200
DEQUEST
0.80
28.0
22:00
>30:00
211
200
SodaAsh
0.80
26.5
2:35
7:50
211
200
Lime
0.80
26.5
3:15
10:20
Daxad
240
Control
0.0
18.8
2:55
9:00
Daxad
240
DEQUEST
0.80
26.0
12:00
23:00
Daxad
240
SodaAsh
0.80
12.2
<1:30
7:00
Daxad
240
Lime
0.80
17.5
2:30
7:10
For testing, a portion of the slurry was transferred to a Slump Cylinder 2 inches (5 cm) in diameter and four inches (10 cm) tall and a 7 ounce (207 cc) cup. Contents of the cylinder were screeded flush with the top of the cylinder. If compression strength and temperature rise set measurements were taken, additional slurry was poured into brass two inch cube molds and an insulated cup. Sixty seconds from the start of the stucco soak, the slump cylinder was raised with a pneumatic mechanism. The diameter of the resultant patty was measured in at least two directions and recorded as the average of the two readings. “Stiffening time” is measured as the elapsed time from the beginning of the stucco soak to when a Vicat needle drawn through the slurry left a definite line that did not flow back. The stiffening time is a measure of the hydration of the slurry. “Vicat set” refers to the elapsed time from the onset of the stucco soak until a 300 gram Vicat needle positioned at the surface of the 7 ounce cup fails to penetrate to the bottom of the sample.
As shown in the data above, the addition of DEQUEST 2006 and Soda Ash each resulted in an increase in fluidity of the slurry as indicated by the increase in patty size over the control sample. DEQUEST 2006 increased patty size with both 211 (polycarboxylate) and Daxad (naphthalene sulfonate) dispersants.
Example 2
Additional laboratory tests were conducted where accelerator was added to reduce the retardive effects of the dispersant. The slurry was made more similar to a wallboard slurry by the addition of foam.
One hundred twenty grams of landplaster and water as shown were added to a Hobart Model N-50 mixer followed by addition of the additive. The mixer was turned on low (setting 1) for five minutes. The amount of dispersant was enough to give 1.8 grams of solids. The dispersant was weighed out on a small plastic boat and added to the mixture by hand. One thousand eighty grams of stucco were then added to the mixer and allowed to soak for 15 seconds. The slurry was mixed on medium speed (setting 2) for 15 seconds.
TABLE II
Water,
Amt.,
Patty Size,
Dispersant
grams
Additive
grams
cm
Stiff Time
211
600
Control
0.0
20.7
2:15
211
600
DEQUEST
0.60
25.5
2:50
211
600
TSP
0.60
22.5
2:30
211
600
TSPP
0.60
25.0
2:40
Daxad
720
Control
0.0
13.2
<1:50
Daxad
720
DEQUEST
0.60
17.1
1:45
Daxad
720
TSP
0.60
14.0
1:20
Daxad
720
TSPP
0.60
15.2
2:10
Other dry additives, such as set accelerators or starches, are preferably combined with the stucco prior to entry to the slurry. Wet additives are generally added directly to the mixer prior to introduction of the dry components. When all components are added, the resulting slurry is mixed until a homogeneous slurry is obtained.
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A gypsum slurry includes calcium sulfate hemihydrate, water and calcium sulfate dihydrate is coated with a hydrophilic, dispersible coating. The coating is less soluble than the calcium sulfate hemihydrate to delay exposure of the landplaster to the remainder of the slurry, preventing premature crystallization and the early stiffening that accompanies it.
Another embodiment is a gypsum slurry that includes calcium sulfate hemihydrate, a polycarboxylate dispersant, water and coated calcium sulfate dihydrate. In this case, the hydrophilic, dispersible coating is selected to serve as a modifier to enhance the ability of the dispersant to fluidize the gypsum slurry.
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BACKGROUND OF THE INVENTION
The present application is a continuing application of copending application U.S. Ser. No. 07/076,625, filed July 23, 1987, now abandoned, which was a continuing application of U.S. Ser. No. 894,910, filed Aug. 8, 1986, now abandoned, which was a continuing application of U.S. Ser. No. 643,023, filed Aug. 21, 1984, now abandoned.
1. FIELD OF THE INVENTION
This invention relates to a new pharmaceutical composition useful for the treatment of pyrexia and inflammation. More particularly, this invention relates to a tripeptide sequence contained in alpha-Melanocyte Stimulating Hormone and ACTH which has been identified as an antipyretic and anti-inflammatory agent.
2. DESCRIPTION OF THE RELATED ART
There are two classes of agents presently in common usage as antipyretic agents, the salicylates and the para-aminophenol derivatives. The salicylates, characterized by acetylsalicylic acid (i.e., aspirin), are the most extensively employed antipyretic agents. Aspirin is the prototype for both the salicylates and other drugs with similar effects and is the standard of reference for comparison and evaluation of these agents. The anti-pyretic effect of aspirin is usually rapid and effective in febrile patients. The salicylates act to reset the "thermostat" for normal temperature.
Although aspirin is generally well-tolerated by most individuals, a number of toxic side effects are associated with its use. Of particular concern is salicylate-induced gastric ulceration and sometimes hemorrhage. Exacerbation of peptic ulcer symptoms (heartburn, dyspepsia), gastro-intestinal hemorrhage, and erosive gastritis have all been reported in patients taking aspirin. Other less common side effects include tinnitus and hearing loss, changes in acid-base balance and electrolyte pattern, and respiratory alkalosis. Although generally such side effects are not particularly dangerous, they tend to reduce patient compliance. Other salicylate derivatives, which are generally employed for their analgesic and/or anti-inflammatory activity, demonstrate increased toxicities relative to aspirin.
The para-aminophenol derivatives, acetaminophen and phenacetin, are alternatives to aspirin for its analgesic and antipyretic uses. Acetaminophen has somewhat less overall toxicity and is generally preferred over phenacetin. Because acetaminophen is well-tolerated and lacks many of the undesired effects of aspirin, it has been gaining favor as the "common household analgesic." However, its suitability for this purpose is questionable: in acute overdosage, acetaminophen can cause fatal hepatic necrosis. In addition, phenacetin may cause methemo-globinemia and hemolytic anemia as a form of acute toxicity, but more commonly as a consequence of chronic overdosage. These agents are about equipotent with aspirin in the treatment of pyrexia.
Recent advances in the study of alpha-Melanocyte Stimulating Hormone (hereinafter referred to as "MSH") have demonstrated that this protein is active in the treatment of pyrexia. Alpha MSH is a 13-amino acid peptide derived from Adrenocorticotropic Hormone ("ACTH"). Both MSH and ACTH share a 13-amino acid sequence that is effective in modulating body temperature. There is evidence that these neuropeptides can influence centrally mediated processes, including central control of body temperature. Both peptides lower core temperature of afebrile rabbits when given peripherally or centrally in sufficient dosages. Much smaller dosages reduce fever without altering normal temperature.
Alpha MSH is found in brain regions that govern temperature regulation, including the anterior hypothalumus and the septum. The concentration of alpha MSH in the septum rises during fever, and the concentration in the arcuate nucleus tends to decline at the same time. Studies comparing the antipyretic activity of centrally-administered alpha MSH to the widely-used antipyretic, acetaminophen indicate that alpha MSH is much more potent in reducing fever than acetaminophen, and that alpha MSH was more than 2500 times more potent by weight than acetaminophen in reducing fever. No endogenous substance other than ACTH is known to have such potency in reducing fever.
The antipyretic potency of alpha MSH and the fact that this peptide reduces fever even when given peripherally may have clinical significance. ACTH was used to reduce clinical and experimental fever soon after it was first described, but this peptide also stimulates cortico-steroid release, and can, with repeated administration, result in Cushing's syndrome. On the other hand, the shorter alpha MSH molecule, which is derived from ACTH, does not stimulate steriod release and there appears to be no irreversible deleterious effects when given to rabbits or to man.
With respect to ACTH (amino acids 1-39 of proopio-cortin), it has previously been known that due to its corticosteroid stimulatory effect, this protein was active in the treatment of inflammation. However, shorter ACTH-related peptides such as alpha-MSH (amino acids 1-13 of ACTH) which do not exhibit corticotropic activity have not been shown to have anti-inflammatory action, and there has previously been no basis to suggest such a role for peptides which correspond to amino-terminal portions of ACTH yet which exhibit no corticotropic activity.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition useful in the treatment of pyrexia and inflammation. The active component of this pharmaceutical composition is a peptide which includes an amino acid sequence corresponding to amino acids 11 through 13 of alpha MSH, lysine-proline-valine ("lys-pro-val"). In its most general scope, the invention is directed to peptides of from 3 to 13 amino acids, which peptides have sequences corresponding to that of alpha-MSH and include at least the lys-pro-val sequence thereof. In more particular embodiments, the invention is directed to the tripeptide itself.
Preferably, the tripeptide itself is administered to achieve maximal benefits in accordance herewith, preferably in a biologically "protected" form. When the tripeptide is "protected" through acylation of the amino terminus and/or amidation of the carboxyl terminus, the resulting tripeptide demonstrates an increase in pharmacologic activity. Similarly, when the tripeptide, whether "protected" or "unprotected", is co-administered with copper ion, a further increase in antipyretic activity is observed.
The present invention provides a method for treating pyrexia and/or inflammation in an individual in need of such treatment in which an effective dose of a peptide which includes the tripeptide sequence is administered to the pyretic individual. Moreover, such peptides may be used in the treatment of both generalized or localized inflammation and, therefore, is a useful alternative to steroidal and salicylate anti-inflammatory agents. Anti-inflammatory activity is observed following administration of the tripeptide to animals at doses approximately equal or greater than those used to demonstrate antipyresis, and testing the reactivity of treated and control animals to inflammatory challenge. Therefore, the peptides of the present invention may be used both as an antipyretic and as an anti-inflammatory agent when administered at a selected dose to a patient in need.
In particular embodiments herein, doses of the tripeptide effective for the expression of anti-inflammatory activity, for example, for the reduction of inflammation-associated swelling and/or capillary permeability, are shown to be roughly similar on a weight basis to those of hydrocortisone, an accepted standard for anti-inflammatory activity. The sensitive "skin-blueing"assay was employed to test the ability of the tripeptide to inhibit the capillary permeabilizing effects of inflammatory agents such as histamine. In this assay, the protected Lys-Pro-Val tripeptide exhibited antihistamine effects, and in particular, a reduction in histamine-mediated increases in capillary permeability, at intravenous dosages as low as 1.25 ug protected tripeptide/kg body weight. Moreover, in the traditional carrageenan/rat paw edema test, intraperitoneally-administered tripeptide demonstrated an ability to inhibit carrageenan-induced swelling of rat paws on a per weight basis commensurate with hydrocortisone. Accordingly, from such observations it can be concluded that the tripeptide lys-pro-val is an effective anti-inflammatory when administered to a patient at a dose ranging from as low as 1 to 10 ug/kilogram, to preferred ranges of on the order of about 0.2 to about 3 mg/kg/day.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1. Amino acid sequence of alpha-MSH
FIG. 2. Comparison of inhibition of paw swelling caused by Ac--Lys--Pro--Val--NH 2 (100 mg/kg) and hydrocortisone (100 mg/kg) in rats. Each score is the mean % change in paw volume relative to the change in matched control paw volume.
DETAILED DESCRIPTION OF THE INVENTION
Peptides used in the practice of the present invention include the sequence lysine-proline-valine. This tripeptide sequence is characterized as follows.
In its naturally occurring form, the tripeptide sequence (lysine-proline-valine) comprises amino acid numbers 11-13 of alpha-Melanocyte Stimulating Hormone (hereinafter "MSH") and ACTH. This finding may explain the antipyretic activity of the amino-terminal portion of ACTH (amino acid numbers 1-24 of proopiocortin) and MSH (amino acid numbers 1-13 of ACTH and proopiocortin; see FIG. 1), both of which exhibit the tripeptide sequence within their structure. Therefore, both MSH and ACTH represent potential naturally occurring sources from which the antipyretic tripeptide can be obtained, or, in the case of alpha-MSH, which can be used directly in accordance with less preferred embodiments.
Due to the high corticotropic effect of ACTH, which can lead to incidences of Cushing's Syndrome, the invention is generally directed to the alpha-MSH sequence and peptides thereof, so long as such peptides include at least the lys-pro-val sequence. This is based on the finding that alpha-MSH (amino acids 1-13 of ACTH) does not exhibit the corticotropic effect of ACTH and, instead, appear to exert their anti-inflammatory action directly rather than through a corticosteroid intermediate.
In preferred embodiments, the tripeptide can be isolated from MSH. This can be accomplished by first fragmenting the MSH protein into four smaller peptides through total digestion with the proteolytic enzyme, chymotrypsin. Paper electrophoresis of the digestion products reveals four major products, one of which is the tetrapeptide, glycine-lysine-proline-valine, which may be used directly. However, the glycine residue can be removed by partial acid hydrolysis to yield the tripeptide.
Peptides in accordance with the invention can also be obtained by chemical synthesis. This is accomplished by way of peptide bond formation between the appropriate amino acids. Amino acids are amphoteric molecules which contain both an acidic (--COOH) moiety and a weekly basic (--NH 2 ) moiety. Peptide bond formation (--CONH--), therefore, is accomplished through a nucleophilic attack of the amine group on the carboxylic function.
In forming a peptide bond between two hypothetical amino acids, X and Y, four possible dipeptides may be produced: X--Y, Y--X, Y--Y, and X--X. Therefore, in order to reduce the possible structures that may be formed in such an interaction, the amino or carboxy terminus of the appropriate amino acid must be first "protected" so as to preclude a reaction involving the "protected" moiety. For example, if "c" represents a protected carboxy terminus and "n" a protected amino terminus, then an interaction involving cX and Yn could generate only one structure, cX--Yn.
However, in order to be chemically useful for synthetic purposes, the protecting groups must be removable. In general, carboxy groups can be protected by esterification or amidation of the --COOH to --COO--alkyl or --CONH 2 . The preferred alkyl groups for the carboxy terminus include methyl and benzyl residues, yet other alkyl groups, such as ethyl, propyl, butyl, p-nitrobenzyl or p-methoxybenzyl groups, can be utilized.
Likewise, the amino terminus is protected by acylation, introducing a carboxyl group such as an acetyl group, t-butyloxycarbonyl group, t-amyloxycarbonyl group, o-nitrophenylsulfenyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, tosyl or formyl group.
Protecting groups may also serve a function in nature. Bioactive peptides which contain an acetyl group bound to be amino-terminus of the peptide and an amido function bound to the carboxy-terminus are less susceptible to acid hydrolysis. Furthermore, it has been speculated that such groups play a role in reducing the susceptibility of the "protected" peptide to enzymatic attack and degradation. Accordingly, a "protected" tripeptide has been synthesized which contains these protecting groups. This protected tripeptide is more active pharmacologically than the unprotected tripeptide.
The various distinct pharmacological actions of the tripeptide, i.e., anti-inflammation and antipyresis, are demonstrated herein through the use of accepted pharmacological assays. For example, antipyretic action is demonstrated using an in vivo rabbit pyresis assay in which increasing amounts of a protected tripeptide (acetyl-lys-pro-val-NH 2 ) was administered to pyrogen-induced rabbits. In this assay, an effective dose range of on the order of 10 ug to 100 mg/kg for the unprotected tripeptide was observed, resulting in fever reductions over control of on the order of about 25% to about 70%, in a generally dose dependent fashion. Moreover, the protected tripeptide (diacetyl-lys-pro-val-NH 2 ) exhibited an activity approximately twice the activity of the unprotected species on a weight basis.
The anti-inflammatory action of the tripeptide is demonstrated employing accepted in vivo assays designed to test the ability of a test agent in inhibiting various symptomology of inflammation, including tissue swelling (e.g., localized edema) and capillary permeability.
In one assay, the skin-blueing test, the tripeptide was tested for its ability to inhibit the capillary permeabilizing effects of histamine by its action in blocking the effects of exogenous histamine. Using this assay, which has been found by the present inventors to be sensitive to low amounts of the agent, it was found that dosages as low as about 1 microgram of the protected tripeptide/kilogram elicited a demonstrable effect as measured by reduction in histamine-mediated increase of vascular permeability to vital dyes.
In a second test, referred to in the art as the carrageenan/rat paw edema assay, the tripeptide is shown to achieve an anti-inflammatory action roughly equivalent to that of a well-known anti-inflammatory agent, hydrocortisone. In this assay, rats were first administered equal intraperitoneal doses of either control (saline), of tripeptide or of hydrocortisone. The paw of the rat was then challenged with an antigenic substance, generally carrageenan, and the resultant swelling measured and data compared. From such assays, it was found that approximately equal weights of the protected tripeptide (diacetyl-Lys-Pro-Val-NH 2 ) and hydrocortisone resulted in a roughly equivalent overall response in reducing the degree of carrageenan-induced swelling.
Based on the foregoing and additional observations, it is found that dosages on the order of 0.2 to about 3 mg of protected tripeptide per kilogram body weight per day will result in advantages in accordance with the present invention in terms of effective anti-inflammatory action. Generally, it will be preferred to administer doses of on the order of 0.35 and about 1.5 mg of protected tripeptide/kg body weight/day to achieve the greatest degree of anti-inflammatory benefit. These dose ranges are derived from the aforementioned observation of approximately equipotentcy of the tripeptide and hydrocortisone, and the general knowledge in the art regarding effective dose ranges of hydrocortisone (see, e.g., Goodman et al. (1985), The Pharmacological Basis of Therapeutics, 7th Edition).
In accordance with the invention, it will generally be preferred to administer the tripeptide parenterally, for example, intramuscularly or intravenously. However, due to its small size, membrane permeability and relatively acid-stable structure, it will be recognized that the tripeptide may be administered orally, albeit at somewhat higher doses. In this regard, it is believed that doses of on the order of about 0.2 to about 3.5 mg/kg/day will achieve benefits in accordance herewith
Pharmaceutical preparations of the tripeptide, preferably a protected tripeptide such as diacetyl-Lys-Pro-Val-NH 2 , comprise generally the active agent in combination with pharmaceutically acceptable buffers, diluents, stabilizers and the like. For a fairly complete listing of various techniques, including a variety of agents and additives useful in the preparation of acceptable pharmaceutical compositions, one may wish to refer to Remington's Pharmaceutical Sciences, 16th ed., 1980, Mack Publishing Co., incorporated herein by reference.
In a preferred pharmaceutical composition, approximately 100 to 500 mg of diacety-Lys-Pro-Val-NH 2 is dispersed in about 1 to 7 cc. of sterile isotonic saline, including a pharmacologically accepted buffer to maintain a pH of about neutral. For intravenous administration, for example, to a patient suffering from arthritis, or severe allergic reaction or various other diseases involving inflammatory processes, it will generally be desirable to administer about 0.2 to about 3.5 mg/kg/day of the agent by slow infusion over a period of time (up to several hours). Where infusion is impractical, the agent is administered in the form of an intramuscular injection, preferably in combination with a lipophilic carrier and at somewhat higher doses. For the treatment of mild to severe arthritic episodes, it is generally recommended that a parenteral dose of on the order of about 0.3 to 1.5 mg/kg/day, preferably about 0.5 to about 0.6 mg/kg/day. However, for severe allergic reactions, higher doses on the order of about 2.5 to up to about 4 mg/kg/day may be indicated.
It is believed that many changes may be made in the amino acid sequence of the peptides of the present invention and still obtain a protein which exhibits a biologically functional equivalent pharmacologic activity. For example, it has been found by Kyte et al. (1982), J. Mol. Biol., 157:105, that certain amino acids may be substitute for other amino acids having a similar hydropathic index, and still retain the biologic activity of the protein. As displayed in the table below, amino acids are assigned a hydropathic index on the basis of their hydrophobicity and charge characteristics. It is believed that the relative hydropathic character of the amino acid determines the secondary structure of the resultant protein, which in turn defines the interaction of the protein with its receptor.
In the case of the present peptides, it is believed that biological functional equivalents may be obtained by substitution of amino acids having similar hydropathic values. As used herein, a biological functional equivalent is defined as a protein that is functionally equivalent in terms of biological functional equivalent is defined as a protein that is functionally equivalent in terms of biological activity. Thus, for example, isoleucine of leucine have a hydropathic index of +4.5 and +3.8, respectively, can be substituted for valine (+4.2), and still obtain a protein having like biological activity. Alternatively, at the other end of the scale, lysine (-3.9) can be substituted with arginine (-4.5), and so on. In general, it is believed that amino acids can be successfully substituted where such amino acid has a hydropathic score of within about +/-1 hydropathic index unit of the replaced amino acid.
______________________________________Amino acid Hydropathic Index______________________________________Isoleucine 4.5Valine 4.2Leucine 3.8Phenylalanine 2.8Cysteine/cystine 2.5Methionine 1.9Alanine 1.8Glycine -0.4Threonine -0.7Tryptophan -0.9Serine -0.8Tyrosine -1.3Proline -1.6Histidine -3.2Glutamic Acid -3.5Glutamine -3.5Aspartic Acid -3.5Asparagine -3.5Lysine -3.9Arginine -4.5______________________________________
The following examples illustrate experiments conducted by the present inventor to illustrate the production of the preferred tripeptide, as well as various "protected" species, and use of the tripeptide in various accepted in vivo assays which demonstrate its activity. It will be appreciated that these examples are illustrative only and variations may be made in light thereof and in light of the level of skill in the art. Thus, for example, where peptides having different sequences, or longer or shorter peptidyl length, are desired, it will be apparent to those of skill in the art that the procedures generally as set forth below may be employed. Accordingly, where the sequence arg-pro-val is desired (a biologically functional equivalent of lys-pro-val), it will be apparent that dibenzyloxycarbonyl-confugated arginine ("Z-arg") should be employed in the place of "Z-arg") . Moreover, where, for example, gly-lys-pro-val is desired, it will be apparent that "Z-gly" should be employed as the starting reagent and synthetic steps employed as set forth to sequatically add the lys, pro and val residues, respectively. These and all other modifications to achieve the various peptides are well known and will be apparent to those of skill.
EXAMPLE I
Chemical Synthesis Of L-Lysine-L-Proline-L-Valine L-PROLINE-L VALINE
The tripeptide was custom synthesized by Bachem, Inc., Torrance, Ca., as follows:
1. Z-Lys-Pro-OMe Preparation
50 mmoles (20.7 grams) of dibenzyloxycarbonyl-conjugated lysine ("Z-lys") in 200 ml of methylene chloride was combined with 50 mmoles (8.3 grams) of proline methyl ester (pro-OMe) in 100 ml dimethyl formamide. The mixture was added to a conical flask and cooled to -5° C. with stirring. 50 mmoles (5.5 ml) of N-methyl morpholine was added, followed by the addition of 10.3 grams of dicyclohexyl-carbodiimide in 20 ml of methylene chloride and the reaction mixture was stirred overnight. The mixture was then filtered from urea and the filtrate concentrated in vacuo. The residue was taken up in ethyl acetate and washed successively with sodium bicarbonate solution, water, IN hydrochloric acid, and water. Ethyl acetate was removed in vacuo and the oily product was saponified without purification.
2. Removal of the -OMe Carboxy Terminus "Protecting " Group.
The oily product from the previous experiment was dissolved in methanol (200 ml) and treated with 2N sodium hydroxide (25 ml) for an hour. Methanol was removed under reduced pressure and the residue was taken up in water and acidified with 6N hydrochloric acid. The product was extracted with ethyl acetate, and the organic layer was washed with water and dried over sodium sulphate. Ethyl acetate was removed in vacuo and the residue was triturated with hexane. The product was checked by thin layer chromatography using chloroform: methanol: acetic acid (95:4:1).
3. Preparation of Z-Lys-Pro-Val-OBe
The next step in the synthesis of the tripeptide involved the addition of a carboxy-protected valine residue (Val-OBe). The protecting group in this instance was a benzyl ester.
37 mmoles (19 grams) of Z-Lys-Pro obtained from step 2 above was dissolved in 200 ml distilled tetrahydrofuran. This solution and 4.1 ml N-methyl, morpholine were mixed together and cooled to -15° C. with stirring. Isobutyl-chloroformate (5)(ml) was added and the mixture stirred for 5 minutes at -10° C. Concurrent with the above, 35 mmoles (13.2 grams) of valine benzyl ester tosylate was dissolved in 100 ml dimethyl formamide. The mixture was cooled to -10° C. and neutralized with N-methyl morpholine (4 ml). This was added to the above mixed anhydride and stirred overnight. The mixture was then filtered from urea and the filtrate concentrated in vacuo. The residue was taken up in ethyl acetate and washed successively with sodium bicarbonate solution, water, 1N hydrochloric acid, and water. The crude product was purified on a silica gel column using chloroform-methanol (95:5). Fractions containing the pure product were determined by thin layer chromatography utilizing the same solvent as for step 2. The appropriate fractions were pooled.
4. Removal of the Protecting Groups Z- and -OBe
9 grams of the protected tripeptide produced in step 3 above was hydrogenated in an acetic acid-water-methanol mixture in the presence of Pd/BaSO 4 overnight. It was filtered from the catalyst and the filtrate was evaporated in vacuo to give an oily residue. This was triturated with absolute ethanol and absolute ether to yield 3 grams of the crystalline product. The product was checked by thin-layer chromatography using a solvent system composed of butanol: acetic acid: water: pyridine (20:6:11:24).
Chemical Synthesis of diacetyl-L-Lysyl-L-Prolyl-L-Valyl-NH 2
The protected tripeptide, diacetyl-L-Lysyl-L-Prolyl-L-Valyl-NH 2 can also be prepared by the chemical techniques described above in steps 1-3. For example, in step 1, the starting material would be diacetyl conjugated lysine. In step 3, the valine-benzylester is substituted with valyl-amide.
EXAMPLE II
Antipyretic Activity of L-LYS-L-PRO-L-VAL
Production of Leukocytic Pyrogen
Leukocytic pyrogen is a molecule capable of producing transient fever in mammals which is produced by incubating rabbit leukocytes with Salmonella typhosa endotoxin. More specifically, to produce leukocytic pyrogen, donor rabbits were first sacrificed by decapitation. Blood was collected in a heparinized pryrogen-free beaker. Heparinized 50-ml glass centrifuge tubes were filled 3/4 full with whole blood, saline was added to fill each tube, and the solution was gently mixed. The tubes were then centrifuged at low speed for 20 min. The buffy coat was drawn off and placed in pyrogen-free flasks. Lactate Ringer's solution equal in volume to one-half that of the red cell layer, was added along with Salmonella typhosa endotoxin (Difco, No. 0901) also in Ringer's solution (1 ug/ml), to the buffy coat. The mixture was incubated at 38° C. in a shaking water bath for 4 hours. The solution was centrifuged, filtered (Nalgene, 0.20 microns), and the leukocytic pyrogen-containing filtrate was stored at 4° C. Samples of leukocytic pyrogen were heated to 70° C. for 2 hours and injected intravenously to test for endotoxin contamination. Only characteristic leukocytic pyrogen fevers occurred and no prolonged fevers were observed, indicating that the leukocytic pyrogen was free of endotoxin and other heat-stable pyrogens.
Injections were 50 ul in volume and were followed by a 20 ul saline flush. Intravenous injections were made via the marginal ear vein. Intravenous leukocytic pyrogen injections were 0.07 ml of a stock solution made up of a mixture of leukocytic pyrogen derived from 4 donors. When injected, leukocytic pyrogen stock solution was diluted with nonpyrgenic isotonic saline. Injections were made with commercial nonpyrogenic syringes. Glassware was washed with chromic acid, rinsed with deionized water and to 200° C. for a minimum of 2 hours to insure that it was pyrogen free.
Animal Procedures
Adult New Zealand white rabbits were used for the development of an antipyretic assay. The rabbits were housed individually in a 21°-23° C. enVironment with a 12 hour light/dark cycle; food and water were available ad libitum. Central nervous system injections of the anti-pyretic agents were performed as follows: The animals were pretreated with ketamine hydrochloride and promazine (Ketaset Plus, Bristol Labs, 0.4 ml/kg. intramuscularly) and anesthesia was induced and maintained by inhalation of methoxyfluorane (Metafane, Pitman-Moore, Inc.) and an N 2 O--O 2 mixture. Rabbits were placed in a Kopf rabbit stereotaxic instrument and a stainless steel cannula (No. 201, David Kopf Instruments) was inserted into a lateral ventricle at a point 1.0 mm anterior to the bregma and 2.7 mm lateral to the midline. The cannula was lowered until cerebrospinal fluid appeared inside the well of the cannula. Stainless steel screws and dental acrylic were used to anchor the cannula to the caluarium. Benzathine penicillin G (Bicillin, Wyeth Laboratories) was given post-operatively (150,000 units intramuscularly).
Experimental rabbits that were to be used in the antipyresis study were restrained in conventional holders and a thermistor probe (Yellow Springs International, No. 701) was inserted about 100 mm into the rectum and taped to the tail. In certain experiments, another thermistor probe (Yellow Springs International, No. 709) was attached to the dorsal surface of the ear. Temperature recordings were made every 10 minutes via a MINC 11 online computer connected to a digital temperature recorder (Datalogger, United Systems Corp.) At least 1 hour was allowed after the probes were inserted before injections were made, and all experiments were separated by at least 48 hours. Experiments were run in an environmental chamber at 23° C.
The average thermal response, the mean change in temperature (°C.) over the duration of the response measured in hours, was calculated for each response and the paired t-test was used for statistical analysis of the data. The time period over which the experimental anti-pyretic temperature response was determined was generally set by the duration of the control response for the individual animal. The control response begins with the first deviation from baseline temperature and continues until the temperature returns to baseline or to the point nearest the baseline within 5 hours. The mean change in temperature for each 10 minute intervals during this time period are summed and divided by the total number of 10 minute periods.
Assay Protocol and Results
Immediately after the tripeptide, L-Lys-L-Pro-L-Val, was synthesized as described above, it was dissolved in sterile non-pyrogenic isotonic saline and stored frozen in aliquots until just prior to use. Before any injections of the tripeptide were given, leukocytic pyrogen was tested in each animal in order to establish its sensitivity to the pyrogen and to test for endotoxin activity.
To induce fever in the test animals, 0.15 ml of a stock solution of leukocytic pyrogen was injected into a marginal ear vein. Pyrogen from several batches was used, but each animal received pyrogen from the same batch throughout each series of experiments.
Injections of the tripeptide were given 30 minutes after the pyrogen, into the intraventricular cannula. Centrally administered tripeptide resulted in an observed antipyresis. Decreases in fever, calculated as percent reduction of the area under the control fever curve over the apparent duration of action of the peptide (1.5 hours), were 24%, 31%, and 48% for the 0.5, 1.0, and 2.0 milligram doses, respectively. Similarly, intravenous administration of 2, 20 and 200 milligrams of the tripeptide reduced fever 34, 27 and 67% , respectively, during the 1.5 hour period after injection of the leukocytic pyrogen. Control saline injections, centrally administered, caused no significant reduction in body temperature. Similarly, when injections of 200 milligrams were given to afebrile rabbits, no reduction in body temperature was observed.
EXAMPLE III
Antipyretic Activity of The Protected Tripeptide Diacetyl-L-LYS-L-PRO-L-VAL-NH 2
Central administration of the acetylated and amidated tripeptide diacetyl-L-Lysine-L-Proline-L-Valine-NH 2 resulted in an increase in the observed antipyresis as well as an increase in the duration of action. Fever induced by intravenous administration of leukocytic pyrogen was reduced more than 50% by 0.5 mg of the protected peptide. The duration of action was at least four hours compared to 1.5 hours observed for the unprotected tripeptide (see Example I). Smaller doses of the protected tripeptide resulted in correspondingly lower antipyresis.
EXAMPLE IV
Antipyretic Activity of Diacetyl-L-LYS-L-PRO-L-VAL-NH 2 and Copper Ion
When 0.5 mg of the protected peptide was given centrally and copper ions (1-10 mg of the cupric chloride salt) were given either centrally or peripherally, the antipyretic effect was greatly augmented and hypothermia developed that was similar to that that has been observed with large doses of the parent alpha-MSH peptide. The protected peptide thus appears to be at least four times more potent than the unprotected tripeptide. The addition of copper ions, in doses that have no effect on normal temperature, markedly enhanced the antipyretic, and hypothermic, effects of the protected peptide.
EXAMPLE V
Anti-Inflammatory Activity
The anti-inflammatory activity of the tripeptide was demonstrated through the use of an animal model developed by Sparrow and Wilhelm (1957), J. Physiol., 137:51-65, incorporated herein by reference. This model relies on the principal that localized, subcutaneous injections of histamine will result in a localized increase in capillary permeability. When the test animal has been pretreated with blue dye intravenously, the localized histamine injections will elicit blue-colored "weals" around the injection site. Thus, by preadministration of an effective anti-inflammatory agent, the blue color of the histamine-induced weals will be much less pronounced, with the amount of color reduction being dependent on the relative amount and/or potency of the anti-inflammatory agent used.
Non-moulting New Zealand white rabbits were used for the Sparrow/Wilhelm assay. The skin of the rabbits back was closely clipped 1-2 days previous to the experiment, but not dipilated, and the rabbits were kept warm until tested. Various amounts of the protected tripeptide (diacetyl-L-lys-1-Pro-L-Val-NH 2 ) were injected intravenously into an ear vein approximately 15 minutes prior to intravenous injection of blue dye. Control rabbits received sham injections. Fifteen minutes following injection of the agent or sham, the rabbits received approximately 30 mg/kg of Pontamine blue dye as a 2.5% solution in 0.45% saline, into an exposed vein.
Immediately following dye injections, histamine was injected intradermally in a 0.10 ml volume (1.25 mg histamine /0.1 ml volume) at several sites on each side of the spine. In all, one vertical row of six injections were made on each side of the spine. The relative intensity of the resultant blue weals were scored by an independent observer 30 minutes after histamine injection. The results are displayed in Table I below.
TABLE I______________________________________Anti-inflamatory Activityof the TripeptideNo. Animals TripeptideTested Dose + Result______________________________________ 3 (2E, 1C)* 5 E lighter than C2 (1E, 1C) 10 E lighter than C2 (1E, 1C) 5 E lighter than C2 (1E, 1C) 1.25 E lighter than C2 (1E, 1C) 0.625 No difference observed______________________________________ *E = experimental; C = control + Dosages in ug of protected tripeptide per kg body weight, administered intravenously.
As will be appreciated from the results displayed in Table I, intravenous doses down to 1.25 ug tripeptide per kg body weight resulted in an appreciable reduction in histamine-induced blue weal formation and is thus indicative of an effective anti-inflammatory action. At doses of 5 and 10 ug/kg, the observed response was even more pronounced. Also as will be appreciated, the anti-inflammatory effect of the tripeptide is observed at relatively lower doses as compared to its anti-pyretic effect.
EXAMPLE VI
Carrageenan/Rat Paw Edema Assay
A second in vivo bioassay for anti-inflammatory activity was conducted in which the action of the tripeptide was compared to that of hydrocortisone. In this assay, the two agents were given at similar doses and tested for their independent ability to inhibit carrageenan-induced swelling of rats paws. This assay, the rat paw edema test, was conducted generally as it is typically performed in the art, for example, as described by Winter et al. (1962), Proc. Soc. Exp. Biol. Med., 111:544 or in U.S. Pat. No. 4,150,137.
Briefly, the assay was performed as follows. Each of twenty-four male Sprague-Dawley rats was assigned to one of four groups: tripeptide treatment and controls (matched according to body weight and initial paw volume), hydrocortisone treatment and matched controls. The volume of the right rear paw of the test and control animals was determined using standard procedures and a mercury displacement volumetric technique. An intraperitoneal injection of the tripeptide (Ac-Lys-Pro-Val-NH 2 , 100 mg/kg, N=6), of hydrocortisone (100 mg/kg, N=6), or saline (matched volume, N=12) was given to each rat. One hour later 0.5 ml of 1% lambda carrageenan in saline solution was injected into the right rear paw of the animals and the paw volume was again recorded (baseline measure). Thereafter paw volume was measured each hour for our hours. For comparison of the effects of the two treatments, paw volume of experimental animals measured at hourly intervals was expressed as a percentage of the volume change of their respective matched controls
The results of this experiment is shown in FIG. 2. As will be appreciated from this data, except for the first hour when hydrocortisone markedly inhibited swelling (<0.05, Mann-Whitney test), there was no significant difference in the inhibition of paw edema caused by the tripeptide and hydrocortisone (>0.20). These results indicated that the tripeptide inhibits inflammation as well as the classic anti-inflammatory agent, when given in an equal dose by weight, albeit with a slight difference in time course. Based on the present results and the known effects of hydrocortisone and inflammation in man, it is concluded that the tripeptide Lys-Pro-Val can be used to reduce inflammation in man, in dosage not markedly different from that of hydrocortisone.
The foregoing invention has been described by way of illustration and example and in terms of standard laboratory techniques employed by the applicant. It will be apparent to those skilled in the art that certain changes and modifications of these procedures may be employed without departing from the spirit and scope of the invention. For example, although chemically synthesized tripeptide was utilized to demonstrate its antipyretic activity, it is contemplated by the inventor that tripeptide isolated from natural sources will function equally well. Moreover, it will be apparent that administration of any copper salt, whether it be the sulfate, chloride, or some other similar copper salt, should be as active as the chloride salt in augmenting the activity of the tripeptide. Similarly, although activity was demonstrated using either intravenous or centrally administered tripeptide, orally administered tripeptide, at higher doses, should be active in reducing fever. It will be apparent to those skilled in the art that these and other modifications and changes are within the scope of the appended claims.
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An antipyretic tripeptide, having the amino acid sequence lysine-proline-valine, and a method for utilizing the tripeptide to reduce fever and inflammation in mammals are disclosed. The tripeptide can either be isolated from natural sources or chemically synthesized. A "protected" tripeptide having greater antipyretic potency and duration of action is also disclosed. The "protected" tripeptide contains an acyl group, such as an acetyl or a dibenzyl oxy carboxyl group, at its amino terminals and is amidated or esterified at its carboxyl terminals. Further, improved antipyretic potency and direction of action can be achieved through the co-administration of copper salts with the tripeptide.
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BACKGROUND OF THE INVENTION
The present invention relates to a method and apparatus for de-aerating liquids, or separating entrained air or froth from liquids or pulps.
The invention has been developed primarily for use with thickeners, clarifiers, or concentrators and will be described hereinafter with reference to these applications. It will be appreciated, however, that the invention is not limited thereto.
Thickeners, clarifiers and concentrations are typically used for separating solids from liquids and are often found in the mining, mineral processing, food processing, sugar refining, water treatment, sewage treated, and other such industries.
These devices typically comprise a tank in which solids are deposited from suspension or solution and settle toward the bottom as pulp or sludge to be drawn off from below and recovered. A dilute liquor of lower relative density is thereby displaced toward the top of the tank, for removal via an overflow launder. The liquid to be thickened is initially fed through a feedline into a feedwell disposed within the main tank. The purpose of the feedwell is to ensure relatively uniform distribution and to prevent turbulence from the incoming feed liquid from disturbing the settling process taking place within the surrounding tank.
In cases where the feed liquid comprises flotation concentrate, it is normally at least partially aerated. The air bubbles, if allowed to pass from the feedwell into the main tank, tend to produce a considerable amount of relatively stable froth on the surface of both the feedwell and the thickener. This froth can contain a significant proportion of entrained solids and thereby tends to reduce the separation efficiency of the thickener. In addition, air bubbles can become trapped in the sludge, resulting in slower settling rates and lower underflow densities, both of which reduce separation efficiency further still.
SUMMARY OF THE INVENTION
It is an object of the present invention to overcome or substantially ameliorate this problem in the prior art.
Accordingly, the invention provides an apparatus for separating froth from liquid, the apparatus comprising a feed conduit to carry partially aerated feed liquid, and a separator to receive and separate the feed liquid into a first component consisting substantially of froth or gas and a second component consisting substantially of de-aerated liquid or sludge.
Preferably, the separator comprises a centrifugal separator adapted to induce rotational flow of the feed liquid in a separation chamber whereby the froth or gas component emerges as overflow from the separator and the liquid or sludge component emerges as underflow from the separator. A bank of separators connected in series, parallel or a combination of both, may be used to achieve the desired level of separation. In one preferred embodiment, the centrifugal separator is a cyclone separator.
The apparatus preferably further includes an array of liquid spray jets positioned to break down any froth following separation into a third component consisting substantially of liquid, which optionally may be added to the second liquid or sludge component downstream of the separator or recycled upstream thereof into the feed liquid.
The present invention also provides a method for separating froth from liquid, the method comprises the steps of conveying a partially aerated feed liquid to a separator, and separating the feed liquid into a first component consisting substantially of froth or gas and a second component consisting substantially of de-aerated liquid or sludge.
Preferably, the feed liquid is separated by means of a centrifugal separator disposed such that the froth or gas component emerges from the separator overflow and the liquid or sludge component emerges from the separator underflow.
The method preferably comprises the further step of breaking down any froth component by means of liquid spray jets into a third component consisting substantially of liquid.
Optionally, the method comprises the further step of recombining the third liquid component with the second liquid component downstream of the separator or with the feed liquid upstream thereof. Alternatively, the overflow and underflow from the centrifugal separator may be directed to separate downstream process units.
In a preferred embodiment, the invention is used to for removal of flotation froth and air from the feed to a thickener. The thickener preferably comprises a tank in which a dispersed solid component tends to settle from solution or suspension toward a lower region of the tank to be drawn off from below whilst a relatively dilute liquor is thereby displaced toward an upper region of the tank for separation via an overflow launder.
BRIEF DESCRIPTION OF THE DRAWING
A preferred embodiment of the invention will now be described, by way of example only, with reference to the accompanying drawing, which is a schematic flow diagram showing the invention as used in conjunction with a thickener.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to the drawing, the invention provides an apparatus 1 for separating liquid from froth. The apparatus comprises a sump 2 adapted to receive feed liquid from an upstream process, and a feed conduit 3 extending from the sump to a separator 4. A pump 5 and valve assembly 6 are disposed within the feed conduit 3 to regulate the flow of liquid. Alternatively, the separator 4 may simply receive feed by gravity flow from the upstream process.
The separator takes the form of a centrifugal separation 4 apparatus which has been found, unexpectedly, to be particularly efficient in separating froth from partially aerated pulps by "shearing" the air bubbles form the solid particles. Whilst a single separator 4 is illustrated, it will be appreciated that a plurality of separators connected in series, parallel or a combination of both, may be used depending upon the throughput, the degree of separation required, and other variables. In one preferred form of the invention, a cyclone type centrifugal separator is used.
Within the centrifugal separator 4, the feed liquid is split between the overflow line 10 and the underflow line 11. The split between these lines 10 and 11 can be controlled as appropriate by varying several operating parameters of the centrifugal separator 4 including the diameter of the separator, the separator length, the angle of the separator barrel, the size of the inlet underflow and internal nozzles, the feed pressure and the feed density. In testing it has been found, somewhat surprisingly, that with a partially aerated feed liquid, and approximately tuned operating parameters, a relatively small overflow stream can be produced which contains the vast majority of the froth, leaving a proportionately large volume of de-aerated underflow liquid having a density similar to that of the feed liquid.
In the preferred embodiment of the invention, the underflow 11 feeds the de-aerated liquid from the centrifugal separator 4 to a thickener (not shown). This obviates the problem of accumulation of excess from in the thickener and the associated feedwell, which in prior art devices significantly reduces the efficiency of the thickening process. The froth stream from the centrifugal separator overflow line 10 is fed to a launder 15 and broken down with fine water spray jets 16. This produces a third components consisting of liquid from the spray jets 16 mixed with the liquid from the collapsed froth, which may be combined with the underflow liquid downstream of the centrifugal separator 4 and thence fed to the thickener, or else recycled to the feed liquid upstream of the centrifugal separator 4.
It has also been found, again quite unexpectedly, that by appropriately controlling various process parameters of the separator 4, including flow rate, viscosity, density, dilution ratio, rotational speed, chamber shape, and the like, the froth can be substantially collapsed within the separator 4 such that the overflow stream consists substantially of gas, in which case the supplementary spray jets 16 are not required.
Of course, it will be appreciated that the centrifugal separator arrangement need not necessarily be applied only to thickeners, since the principle of de-aeration performed by the centrifugal separators may be used in numerous other applications. There is also no specific requirement to recombine the overflow from the centrifugal separator 4 with the underflow or with the feed material. The separated streams may simply be directed to discrete downstream process units as required. There is also no need for pumps if sufficient pressure head is otherwise available.
Although the invention has been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms.
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An apparatus for separating froth from liquid includes a feed conduit to carry partially aerated feed liquid, and a separator to receive and separate the feed liquid into a first component of froth or gas and a second component of de-aerated liquid or sludge.
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The instant application claims the benefit of U.S. Provisional Application Ser. No. 60/195,568 filed on Apr. 7, 2000.
FIELD OF THE INVENTION
This invention relates to the field of optical fibers. More specifically, to the field of devices for removing protective layers from fiber optic cables. Even more specifically, to the field of devices for removing protective layers from fiber optic cables through the use of laser beams.
BACKGROUND OF THE INVENTION
Optical fibers (also simply referred to as “fibers” in this patent) are made of a core, a cladding layer and one or multiple protective coatings or layers. The core material is typically glass or fused silica and the core diameter ranges from a few microns for single mode fibers to a few hundred microns for multi-mode fibers. A cladding material of lower index of refraction such as glass, fused silica or sometimes plastic surrounds the core. The core and cladding material may each be doped to modify the index of refraction of the material or for some other specialized applications such as fiber amplifier and Bragg grating fibers. Finally the fiber is coated with one or more protective layers such as acrylate, silicon acrylate or other materials. These protective layers increase the fiber's mechanical strength and protect it from physical and environmental damage such as that caused by moisture.
Many fiber optics applications require removal of the protective layer. In one example, fibers are stripped at the ends of the fibers to allow fusion splicing of similar or different fiber types, as in the splicing of a specialty fiber such as an erbium doped fiber to a transmission fiber. Fibers are also stripped at the ends to connect an opto-electronic module such as a transmitter, receiver, transceiver, repeater, regenerator, coupler, or wavelength division multiplexer. Any of these modules may require the connection to be hermetically sealed if it may be exposed to harsh environmental conditions. For instance, a wavelength division demultiplexer may be located on the roof or the wall of a building. Fibers with protective coatings such as acrylate can not be directly used in hermetic seals. Polymer to fused silica interfaces and polymer to metal interfaces do not provide true hermetic seals. These interfaces are loosely bonded and susceptible to leaks and degradations. Most polymers are too permeable and degrade and outgas over time. For a true hermetic seal, the fibers must first be stripped of their protective coatings. The naked fused silica is then metalized by evaporation, sputtering, plating or other appropriate metalization means. The metalized fibers are sealed by soldering, which supplies a true hermetic seal between the metalized fibers and the metal case of the module.
The fiber stripping for these purposes is now usually done mechanically with a wire-stripping type tool or by dipping the fiber in the proper chemical etching bath. These methods have several shortcomings. Thermo-mechanical stripping is limited to single fibers and not applicable to ribbons. Furthermore, it is fairly unreliable as the blades wear with usage resulting in incomplete stripping or mechanical damage to the fiber itself. Chemical stripping requires large amounts of highly corrosive acids, which are environmentally unfriendly. Chemical stripping is a fairly slow process, which takes a few minutes including strip, wash and dry. It may leave residues that lead to poor adhesion of the metal film deposited on the fiber. Chemical stripping is difficult to automate. Furthermore, for mid-span stripping, because there is a minimum of fiber bend radius, when dipping the fiber in the chemical etch bath, the strip length is limited to around 15 mm and longer. Shorter strip length is not possible with chemical stripping.
Stripping of fibers in mid-span may also be required. This stripping is much more difficult to achieve than stripping the end of a fiber. For example, to hermetically seal a module with fibers feeding through the box or the connector, it is necessary to first strip the protective coating in the region where the fibers feed through the module enclosure. As described above, stripped fibers provide much better bonding surfaces for the metallized sealant than the protective layer surrounding the fibers. Fibers may also be stripped as a precursor step to writing Bragg gratings. In addition, if the optical fibers are assembled into flat ribbon cables, stripping of the protective layer from a mid-span section of the cable assembly is very difficult with conventional means such as acid bath or thermo-mechanical stripping.
Lasers have been used widely for stripping insulating layers of conventional copper wires. A laser beam is typically incident on the wire and the insulating layer is removed all the way through to the copper core on the side of the wire which is illuminated by the laser beam. The wire or the laser beam is then rotated to remove the protective layer from the other sides of the wire. In that application, the laser energy at a wide range of levels easily ablates the insulator and leaves the copper undamaged. Note that the removal process is very nonuniform because the insulating layer is removed completely from one side, but is left on the other sides of the fibers. Because the fused silica in the fiber form have optical and mechanical characteristics unlike copper, fibers are easily damaged with a similar non-uniform laser process, at laser ablation levels required to remove the protective coatings. Furthermore, as the fused silica transmits some of the laser energy through the fiber, this energy is focused by the fiber itself thus increasing the energy density of the laser beam inside the fiber and outside the fiber on the side of the fiber opposite the illuminating laser beam (see FIG. 1 ). Therefore, using lasers for stripping insulation is a much more complex operation with fiber cables than with copper wires. The process of stripping protective layers from fiber optic cable requires a much more “gentle” stripping process than the non-uniform method used for copper wires.
Moreover, for many applications, even more careful control of the laser energy or wavelength delivered by the optical system is required to strip the protective layer without affecting the index of refraction of the fiber core and cladding. For instance, in Bragg grating fibers, the core contains a dopant such as Germanium or the fiber may be loaded with Hydrogen to allow the writing of the grating on the fiber with UV light exposure. The core of this fiber is sensitive to UV light, and therefore, its index changes with UV exposure.
SUMMARY OF THE INVENTION
This invention results from the realization that a laser can remove the protective layer from the fiber core and cladding more effectively and more reliably than chemical or mechanical means, without significantly damaging the optical and mechanical properties of the fiber and without leaving an excessive amount of residual ablation debris on the fiber while providing careful control of the laser energy. This method thereby allows users to safely strip protective layers off sensitive fibers, such as fibers used for fiber Bragg gratings (FBG).
It is therefore an object of this invention that the protective layer of an optical fiber can be removed with minimum degradation of the optical and mechanical properties of the fiber core and cladding materials.
It is a further object of this invention to provide a method for removal of a protective layer from the fiber core and cladding that is more reliable than removal by mechanical means, particularly when mid-span stripping.
It is a further object of this invention to provide a means for the removal of protective layers of ribbon cable.
It is a further object of this invention that the removal of the protective layers can be performed by a dry, non-contact, reliable, and environmentally friendly method.
It is a further object of this invention that the fiber will not be substantially damaged by the removal of the protective layer.
It is a further object of this invention that unacceptable scoring will not be left on the fiber by removal of the protective layer.
It is a further object of this invention that removal of the protective layer will not leave an excessive amount of residual ablation debris on the fiber.
It is a further object of this invention that the laser energy can be sufficiently controlled to allow effective removal of the protective layer from more sensitive fibers, such as Bragg grating fibers.
It is a further object of this invention that removal of the protective layer from fiber in this manner will leave the fiber in proper condition for metalizing and then sealing the fiber, creating an hermetic seal.
BRIEF DESCRIPTION OF THE DRAWINGS
The novel features believed characteristic of the invention are set forth in the claims. The invention itself however, as well as other features and advantages thereof, will be best understood by reference to the description which follows, read in conjunction with the accompanying drawings, wherein:
FIG. 1 shows a cross section of optical fiber focusing a laser beam.
FIG. 2 shows a cross section of multi-mode fiber covered with one or more protective layers.
FIG. 3 shows a cross section of single-mode fiber covered with one or more protective layers.
FIG. 4 shows a cross section of fiber ribbon cable.
FIG. 5 shows a cross section of fiber covered with one or more protective layers being illuminated on multiple sides by multiple laser beams.
FIG. 6 shows a laser beam being diffused by an optical diffuser.
FIG. 7 shows a laser beam being diffused by a lens array.
FIG. 8 shows a cross section of fiber covered with one or more protective layers being illuminated on multiple sides by multiple laser beams quasi-Lambertian at the fiber.
FIG. 9 shows the cross section of an ablation of the protective layer on a fiber by overlapping laser beams.
FIG. 10 shows homogenization of a laser beam.
DETAILED DESCRIPTION OF THE INVENTION
In the first embodiment, a laser beam 10 , in FIG. 1, is impinging on a fiber 12 while the fiber 12 is spun around its axis 14 . The laser beam 10 can be generated with an excimer laser, a YAG laser, CO 2 laser, diode laser or any other laser source. The laser beam energy density must be sufficient to ablate or remove some of the protective layer 20 , in FIGS. 2 and 3, around the fiber 12 , but low enough to maintain the fused silica material of the core 22 and cladding 24 undamaged. The laser beam typically removes a small fraction of the total thickness (a few microns typically) of the protective layer 20 at every pass. This protective coating “peeling” process ensures a clean and uniform material removal all around the fiber 12 . This technique can be used to remove the protective coating 20 either at the end of the fiber cable 12 (end stripping) or in the middle of the fiber cable 12 (mid-span stripping). The fiber 12 can be translated parallel to its axis 14 to widen the length of the strip area. Fiber ribbon cable 30 , in FIG. 4, can be rotated and translated in similar fashion to remove the protective coatings 36 around the core 32 and cladding 34 of each fiber 38 in the ribbon 30 .
A variation of the present embodiment, shown in FIG. 5, consists of using multiple laser beams 10 (at least two) distributed around the fiber 12 . The fiber 12 in this case does not rotate, but each of the laser beams 10 around the fiber 12 fire simultaneously, sequentially or in some other predetermined pattern to remove the protective coating material 20 around the fiber 12 . This approach is essentially the same as the former technique except that in this case the fiber 12 is kept fixed and the laser beam 10 is distributed around the fiber 10 to remove and “peel” the protective coating 20 around the core 22 /cladding 24 . This technique can be used for end of the fiber 12 stripping or to strip a section in the middle of the fiber cable 12 . The fiber 12 can also be translated in a direction parallel to its axis 14 to widen the length of the strip area. The technique can also be used to strip a section of fiber ribbon cable 30 , in FIG. 4 .
When the laser beam 10 reaches the surface of the fiber 12 , a portion of the beam 10 is focused through the fiber 12 . In particular, if the laser beam 10 is transparent to the fiber 12 , a large amount of the laser energy is transmitted through fiber 12 . The cylindrical nature of the fiber 12 causes the beam 10 to become strongly focused into a small narrow line on the back side 40 of the fiber 12 . Therefore, on the back side 40 of the fiber 12 , the laser beam 10 energy density is strongly increased due to this focusing effect. This high laser 10 energy density may result in unwanted laser damage to the fiber 12 material and may actually result in some cases in scoring of the fiber 12 material. An improvement to the above described embodiment consists in minimizing the focusing effect through the fiber 12 as described below, thus eliminating laser damage to the fiber 12 .
In one embodiment, the laser beam 10 , in FIGS. 6 and 7 is rendered quasi-Lambertian with the use of a spherical lens array or a cross cylindrical lens array 46 or an optical diffuser 48 inserted in the path of the laser beam 10 or any other means that renders a coherent and collimated laser beam 10 quasi-Lambertian in the plane of the fiber 12 .
The purpose of diffusing the beam is to increase the angular distribution or radiance. Ideally a Lambertian distribution is created in the plane of the fiber 12 . A perfect Lambertian source or illumination is such that the radiance (energy per unit area per unit solid angle) is independent of the angle, in other words, any point in the illuminated area is uniformly illuminated from all directions. (Reference: Elements of Modern Optical Design, Donald C. O'Shea, John Wiley and Sons, 1985, pp 92-93). In practice, this is not truly possible but this invention approximates the concept. This illumination is referred to as “quasi-Lambertian”.
With a quasi-Lambertian illumination, the focusing effect of the beam 10 as it propagates into the fiber 12 is greatly reduced. Therefore, the damage to the fiber 12 is greatly reduced if not totally eliminated and the ablation is much more uniform as well.
There are different methods to render a laser beam 10 quasi-Lambertian.
One method to render a beam 10 quasi-Lambertian is to use an optical diffuser 48 or a two-dimensional spherical lens array or cross cylindrical lens arrays 46 . These methods are generally referred to, in this field, as “beam homogenizing” techniques. (This is because these techniques are also used to homogenize, i.e. make more uniform, the intensity distribution of the laser beam over some area.) These methods use one or more optical elements (such as the diffuser 48 or the lens array 46 ) to divide or break the beam 10 into many small beamlets. The multiple small beamlets are recombined in one plane with the use of a condenser lens 54 (see FIG. 10 ). Because the beamlets are recombined at different angles, the angular distribution or radiance of the beam is greatly increased. Therefore, the laser beam homogenizer ( 46 or 48 ) is the preferred method to render the laser beam 10 quasi-Lambertian. With a diffuser 48 (typically a roughened piece of glass or fused silica), the beamlets are totally randomly distributed and a large amount of the energy is lost at high angles and in backscattering and this light is not collected through the condensor lens 54 . With a spherical or cylindrical lens array 46 , the beam is divided in a discrete and well controlled number of little beamlets that are all recollected through the condensor lens 54 . With this method very little laser energy is lost through the optical system.
Another method to render the beam 10 quasi-Lambertian is to use multiple beams 10 (at least two). This is effectively another way to render the beam less directional, i.e. more quasi-Lambertian. By using multiple beams 10 incident on the fiber 12 from different directions, one can basically recreate a quasi-Lambertian illumination with therefore the same benefit, namely reducing laser damage due to focusing through the fiber 12 and more uniform ablation process. This can be done either by using multiple laser sources, or with using one laser source and dividing the beam 10 into multiple branches with beamsplitters (i.e. partially transmissive, partially reflective optical elements) or edge mirrors (i.e. mirrors that only reflect a small fraction of the beam area, while transmitting the rest of the beam). Each of the little beams 10 is then manipulated with individual optical components such as mirrors and lenses and impinge on the fibers 12 from different directions. Note that in this case, each beam 10 follows a separate path and are recombined in the plane of the fiber 12 from different directions substantially uniformly distributed around the fiber. By dividing the laser power density between multiple laser beams, the damaging effect due to focusing of each beam through the fiber is greatly reduced.
When the laser beam 10 is quasi-Lambertian at the plane of the fiber 12 , the effect of focusing through the fiber 12 is minimized. Note that the diffused beam 50 must be quasi-Lambertian rather than just divergent or convergent. Indeed, if the beam 10 is made convergent with the use of a focusing lens for instance, at the level of the fiber 12 , which is only about 125 microns in diameter, the rays are almost parallel and the beam 10 is quasi-collimated as seen through the fiber 12 ; thus, it still exhibits the focusing effect. In the present embodiment, which utilizes a quasi-Lambertian laser beam 50 , the fiber 12 is rotated to remove the protective coating 20 around the fiber 12 . Alternatively, in FIG. 8 multiple quasi-Lambertian laser beams 50 (at least two) can be distributed around a circumference of a cross section of the fiber 12 to remove the protective coating 20 all around the fiber 12 circumference. Each method can be used to strip the protective layers 36 from ribbon cable 30 . In either case, the damage to the fiber 12 material due to the laser beam 50 can be eliminated or at least strongly reduced as compared to the untreated quasi-collimated laser beam 10 . The quasi-Lambertian laser beam 50 technique represents an alternative to the embodiments described above to strip protective coatings 20 / 36 off fiber 12 / 38 .
One specific use of this inventive method involves using an excimer laser beam 10 either with a wavelength of 248 nm (KrF excimer gas) or with a wavelength of 308 nm (XeCl excimer gas). The laser beam 10 is pulsed at a repetition rate between 100 Hz and 200 Hz. This laser 10 delivers between 200 and 600 mJ of laser energy in 15 to 25 ns pulse width. The laser beam 10 is homogenized with two cross-cylindrical lens arrays 46 and a condenser lens 54 . The beam 10 finally is focused through a final lens which reduces its size four times in order to increase the fluence (i.e. the energy per unit area). The fluence or energy density of the beam 10 is between 0.3 and 1 J/cm 2 in the plane of the fiber 10 . The single fiber 10 or the multi-fiber ribbon 30 is mounted on a lathe type apparatus and spun around the axis 14 of the fiber 10 with a rotation rate of approximately 300 revolutions per minute (rpm). Between 200 and 2000 pulses are fired on the fiber 10 while the fiber 10 is spun. Under these conditions, the protective coating 20 of a standard SMF28 optical fiber 10 is removed (125 micron core diameter, 250 micron protective coating 20 diameter) and, at most, minimal damage is done to the mechanical and optical properties of the fiber 12 .
In yet another embodiment, in FIG. 9, two or more laser beams 10 simultaneously impinge on the surface of the fiber 12 at some angle (below 90 degrees) with respect to each other, preferably in a plane substantially perpendicular to the fiber axis 14 . The beams 10 are arranged to overlap in a region 52 on the entrance side of the beam 10 in the fiber 10 . The energy of the two beams 10 adds together in the overlap region 52 on the entrance side through the fiber 12 and provides sufficient energy density to ablate the protective coating material 20 , but is low enough such that it does not create any damage to the fused silica core 22 and cladding 24 of the fiber 12 . On the back side 40 of the fiber 12 there is no overlap, the two beams 10 are separated as they exit the fibers 12 . Although each laser beam 10 exhibits focusing as it passes through the fibers 12 , the beams 10 remain separate on the back side 40 and the energy of the separate lasers 10 does not accumulate on the back side 40 of the fiber 12 . On the back side 40 , the energy of each of the laser beams 10 is maintained low enough such that it does no damage to the fused silica material of the fiber 12 . The reason the energy of the laser 10 can be maintained at a low level, on the back side 40 , is that the energy level of the separate beams 10 at the overlapping region 52 can be maintained below the ablation threshold of the protective layers 20 . Thus ablation would only occur on the protective layers 20 where the separate laser beams 10 overlap. The fiber 12 is rotated around its axis 14 such that the overlapping laser beams 10 remove the protective layers 20 off the fiber 12 . The fiber 12 can be rotated continuously, while the laser beams 10 are firing, or rotated one or more times between intermittent firing times of the laser beams 10 . Alternatively, overlapping laser beams 10 are distributed around the fiber 12 and simultaneously or sequentially fire in order to remove the protective coating 20 off the fiber 12 . These methods can all be used on ribbon cable 30 . The overlapping beam technique represents an alternative over the embodiments described earlier.
It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention.
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This invention results from the realization that a laser can remove the protective layer(s) from the glass or fused silica optical fiber core and cladding more effectively and more reliably than chemical or mechanical means. This invention teaches methods of using laser beams to remove the protective layers of fibers without significantly damaging the optical and mechanical properties of the fiber and without leaving an excessive amount of residual ablation debris on the fiber while providing careful control of the laser energy. This method thereby allows users to safely strip protective layers off sensitive fibers, such as fibers used for fiber Bragg gratings (FBG). This method allows stripping of the protective layers from single fibers and from multi-fiber ribbon cables. It also allows stripping of the protective layers at an end section of the cable or in a middle section (mid-span).
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FIELD OF THE INVENTION
This invention relates to a method for separating p-menthane from p-cymene using certain organic compounds as the agent in azeotropic or extractive distillation.
DESCRIPTION OF PRIOR ART
Extractive distillation is the method of separating close boiling compounds or azeotropes by carrying out the distillation in a multi-plate rectification column in the presence of an added liquid or liquid mixture, said liquid(s) having a boiling point higher than the compounds being separated. The extractive agent is introduced near the top of the column and flows downward until it reaches the stillpot or reboiler. Its presence on each plate of the rectification column alters the relative volatility of the close boiling compounds in a direction to make the separation on each plate greater and thus require either fewer plates to effect the same separation or make possible a greater degree of separation with the same number of plates. When the compounds to be separated normally form an azeotrope, the proper agents will cause them to boil separately during the extractive distillation and this make possible a separation in a rectification column that cannot be done at all when no agent is present. The extractive agent should boil higher than any of the close boiling liquids being separated and not form minimum azeotropes with them. Usually the extractive agent is introduced a few plates from the top of the column to insure that none of the extractive agent is carried over with the lowest boiling component. This usually requires that the extractive agent boil twenty Celcius degrees or more higher than the lowest boiling component.
At the bottom of a continuous column, the less volatile components of the close boiling mixtures and the extractive agent are continuously removed from the column. The usual methods of separation of these two components are the use of another rectification column, cooling and phase separation or solvent extraction.
p-Menthane (1-methyl-4-isopropyl cyclohexane), B.P.=171° C. and p-cymene (1-methyl-4isopropyl benzene), B.P.=175° C. have a relative volatility of only 1.19 and are difficult to separate by rectification. Extractive distillation would be an attractive method of effecting the separation of p-menthane from p-cymene if agents can be found that (1) will enhance the relative volatility between p-menthane and p-cymene and (2) are easy to recover, that is, form no azeotrope with p-methane or p-cymene and boil sufficiently above these to make separation by rectification possible with only a few theoretical plates. Azeotropic distillation would also be an attractive method of separating these two if agents can be found that will enhance the relative volatility sufficiently. p-Cymene can be made by the catalytic dehydrogenation of the saturated ring in p-menthane (1-methyl-4-isopropyl cyclohexane) to convert it into p-cymene (1-methyl-4- isopropyl benzene). Since the conversion is not complete and these two compounds boil only four Celcius degrees apart, separation by distillation is difficult.
The advantage of using azeotropic or extractive distillation in this separation can be seen from the data shown in Table 1 below.
TABLE 1______________________________________Theoretical And Actual Plates Required vs. RelativeVolatility For p-Menthane - p-Cymene SeparationRelative Theoretical Plates Required Actual PlatesVolatility At Total Reflux, 99% Purity Required, 75% Eff.______________________________________ 1.19 53 711.5 23 312.0 13 172.5 10 133.0 8 11______________________________________
The relative volatility of p-menthane to p-cymene is 1.19 and thus require 53 theoretical plates for separation by conventional rectification at total reflux. Plates possessing an efficiency of 75% are commonly employed and thus about 71 actual plates are required, clearly a difficult separation. Several of the agents that I have discovered yield a relative volatility of 2.5 or higher which would reduce the plate requirement to only 13.
Extractive distillation typically requires the addition of an equal amount to twice as much extractive agent as the p-menthane - p-cymene on each plate of the rectification column. The extractive agent should be heated to about the same temperature as the plate into which it is introduced Thus extractive distillation imposes an additional heat requirement on the column as well as somewhat larger plates. However this is less than the increase occasioned by the additional agents required if the separation is done by azeotropic distillation. Another consideration in the selection of the extractive distillation agent is its recovery from the bottoms product. The usual method is by rectification in another column. In order to keep the cost of this operation to a minimum, an appreciable boiling point difference between the compound being separated and the extractive agent is desirable. It is desirable also that the extractive agent be miscible with the p-cymene otherwise it will form a two-phase azeotrope with the p-cymene in the recovery column and some other method of separation will have to be employed.
OBJECTIVE OF THE INVENTION
The objects of this invention are to provide a process or method of azeotropic or extractive distillation that will enhance the relative volatility of p-menthane to p-cymene in their separation in a rectification column. It is a further object of this invention to identify organic compounds that are stable, can be separated from p-cymene by rectification with relatively few plates and can be recycled to the extractive distillation column with little decomposition.
SUMMARY OF THE INVENTION
The objects of the invention are provided by a process for the separation of p-menthane from p-cymene which entails the use of certain organic compounds as the agent in azeotropic or extractive distillation.
DETAILED DESCRIPTION OF THE INVENTION
I have discovered that certain organic compounds will effectively increase the relative volatility between p-menthane and p-cymene and permit the separation of p-menthane from p-cymene by rectification when employed as the agent in azeotropic or extractive distillation. Table 2 lists the agents that I have found to be effective as azeotrope formers with p-methane and remove p-menthane as the overhead product from p-cymene. The data in Tables 2, 3, 4 and 5 were obtained in a vapor-liquid equilibrium still. In every case, the starting material was a mixture of p-menthane and p-cymene in the ratio of about 40% p-menthane, 60% p-cymene. The relative volatilities are listed for each of the agents. The compounds which are effective azeotrope formers to remove p-menthane as overhead from p-cymene are benzyl alcohol, nitrobenzene 3-methyl-1-butanol, 2-methyl-1-butanol, 3-pentanol, isobutanol, 2-butanol, benzonitrile, diethylene glycol ethyl ether and diethylene glycol diethyl ether.
Table 3 lists the agents that I have found to be effective as azeotrope formers with p-cymene and remove p-cymene as the overhead product from p-menthane. The compounds which are effective azeotrope formers to remove p-cymene as overhead from p-menthane are 2-octanol, 1-penthanol, alpha-methyl benzyl alcohol and dipropylene glycol methyl ether.
Table 4 lists the compounds that I have found to be effective extractive distillation agents to remove p-menthane as overhead product from p-cymene. The compounds which are effective are methyl benzoate, butyl benzoate, methyl salicylate, ethyl benzoate, 2-hydroxyacetophenone, acetophenone, ethylene glycol diacetate, benzyl acetate, benzyl benzoate, diethyl maleate, diethylene glycol butyl ether, diethylene glycol hexyl ether, tripropylene methyl ether, benzyl ether
Table 5 lists the compounds that I have found to be effective extractive distillation agents to recover p-cymene as overhead product from p-menthane. The compounds which are effective are glycerol triacetate, isobutyl heptyl ketone 2-undecanone, undecyl alcohol, isodecyl alcohol and cyclododecanol.
TABLE 2______________________________________Effective Azeotropic Agents For Separating p-Menthane Fromp-Cymene, p-Menthane In The Overhead RelativeCompounds Volatility______________________________________None 1.19Nitrobenzene 1.33-Methyl-1-butanol 1.42-Methyl-1-butanol 1.53-Pentanol 5.9Isobutanol 2.42-Butanol 9.1Benzyl alcohol 1.8Benzonitrile 2.8Diethylene glycol ethyl ether 3.8Diethylene glycol diethyl ether 1.5______________________________________
TABLE 3______________________________________Effective Azeotropic Agents For Separating p-Menthane Fromp-Cymene, p-Cymene In The Overhead RelativeCompounds Volatility______________________________________2-Octanol 1.31-Pentanol 2.7alpha-Methyl benzyl alcohol 1.6Dipropylene glycol methyl ether 2.1______________________________________
TABLE 4______________________________________Effective Extractive Distillation Agents For Separatingp-Menthane From p-Cymene, p-Menthane In The Overhead RelativeCompounds Volatility______________________________________Methyl benzoate 1.8Butyl benzoate 2.5Methyl salicylate 1.4Ethyl benzoate 2.32-Hydroxy acetophenone 2.4Acetophenone 1.8Ethylene glycol diacetate 1.5Benzyl acetate 1.5Benzyl benzoate 1.4Diethyl maleate 2.1Diethylene glycol butyl ether 1.4Diethylene glycol hexyl ether 1.5Tripropylene glycol methyl ether 2.7Benzyl ether 1.3Nonyl alcohol 1.8______________________________________
TABLE 5______________________________________Effective Extractive Distillation Agents For Separatingp-Menthane From p-Cymene, p-Cymene In The Overhead RelativeCompounds Volatility______________________________________Glycerol triacetate 1.5Isobutyl heptyl ketone 1.42-Undecanone 1.5Undecyl alcohol 2.9Isodecyl alcohol 1.9Cyclododecanol 3.9______________________________________
Table 6 lists a number of compounds which might have been expected to act favorably in the separation of p-menthane from p-cymene but which failed to yield an effective relative volatility.
TABLE 6______________________________________Ineffective Agents For Separating p-Menthane From p-Cymene______________________________________Dihexyl phthalate 2-Methyl pyrrolidoneEthylene carbonate Propylene carbonateEthyl salicylate Dioctyl sebacateDiethyl malonate n-DecanolHexyl alcohol n-Butanol2-Methyl pentanol 2-Ethyl-1-hexanol2-Ethyl butanol______________________________________
Two of the agents whose relative volatilities had been determined in the vapor-liquid equilibrium still were then evaluated in a glass perforated plate rectification column possessing 7.3 theoretical plates and the results listed in Table 7.
TABLE 7__________________________________________________________________________Data From Runs Made In Rectification Column - p-Menthane From p-Cymene Time Weight % Weight % RelativeAgent Mode Column hrs. p-Menthane p-Cymene Volatility__________________________________________________________________________Isobutanol Azeotropic Overhead 2 99.9 0.1 2.3 Bottoms 68.5 31.5Isobutanol Azeotropic Overhead 4 99.9 0.1 2.4 Bottoms 58.5 41.5Methyl benzoate Extractive Overhead 1 91 9 1.64 Bottoms 21.2 78.8__________________________________________________________________________
Isobutanol was evaluated in the azeotropic distillation mode and gave relative volatilities of 2.3 and 2.4. Methyl benzoate was evaluated in the extractive distillation mode and yielded a relative volatility of 1.64.
THE USEFULNESS OF THE INVENTION
The usefulness or utility of this invention can be demonstrated by referring to the data presented in Tables 2 to 7. All of the successful agents show that p-menthane and p-cymene can be separated one from the other by means of azeotropic or extractive distillation in a rectification column and that the ease of separation as measured by relative volatility is considerable.
WORKING EXAMPLES
1. Forty grams of a p-methane - p-cymene mixture and 20 grams of diethylene glycol ethyl ether were charged to a vapor-liquid equilibrium still and refluxed for five hours. Analysis indicated a vapor composition of 53.7% p-methane, 46.3% p-cymene in the azeotrope; a liquid composition of 23.3% p-menthane, 76.7% p-cymene which is a relative volatility of 3.8.
2. Forty grams of a p-menthane - p-cymene mixture and 20 grams of 1-pentanol were charged to the vapor-liquid equilibrium still and refluxed for four hours. Analysis indicated a vapor composition of 16.8% p-menthane, 83.2% p-cymene in the azeotrope; a liquid composition of 35.2% p-menthane, 65.8% p-cymene which is a relative volatility of p-cymene to p-menthane of 2.7.
3. Forty grams of a p-menthane - p-cymene mixture and 20 grams of butyl benzoate were charged to a vapor-liquid equilibrium still and refluxed for eleven hours. Analysis indicated a vapor composition of 46.1% p-menthane, 53.9% p-cymene; a liquid composition of 40% p-menthane, 60% p-cymene which is a relative volatility of 2.5.
EXAMPLE 4
Forty grams of a p-methane - p-cymene mixture and 20 grams of undecyl alcohol were charged to the vapor-liquid equilibrium still and refluxed for seven hours. Analysis indicated a vapor composition of 34.7% p-menthane, 65.3% p-cymene; a liquid composition of 60.9% p-menthane, 39.1% p-cymene which is a relative volatility of p-cymene to p-menthane of 2.9.
EXAMPLE 5
150 grams of a p-menthane - p-cymene mixture and 200 grams of isobutanol were charged to a glass perforated plate rectification column possessing 7.3 theoretical plates. After two hours at total reflux, overhead and bottoms samples were taken and analysed by gas chromatography. The overhead in the form of the p-menthane - isobutanol azeotrope, was 99.9% p-menthane, 0.1% p-cymene, the bottoms was 68.5% p-menthane, 31.5% p-cymene which is a relative volatility of 2.3. Refluxing gas continued for another two hours. Analysis indicated on overhead in the form of the p-menthane - isobutanol azeotrope of 99.9% p-menthane, 0.1% p-cymene; the bottoms was 58.5% p-menthane, 41.5% p-cymene which is a relative volatility of 2.4. This is data is presented in Table 7.
EXAMPLE 6
A solution comprising 400 grams of the p-menthane - p-cymene mixture was placed in the stillpot of the 7.3 theoretical perforated plate column. When refluxing began, an extractive agent comprising methyl benzoate was pumped into column at a rate of 15 ml/min. The temperature of the extractive agent as it entered the column was 95° C. After establishing the feed rate of the extractive agent, the heat input to the p-menthane - p-cymene in the stillpot was adjusted to give a total reflux rate of 40 ml/min. After one hour of operation, the overhead and bottoms samples of approximately two ml. were collected and analysed. The overhead analysis was 91% p-menthane, 9% p-cymene and the bottoms analysis was 21.2% p-menthane, 78.8% p-cymene. Using these compositions in the Fenske equation, with the number of theoretical plates in the column being 7.3, gave an average relative volatility of 1.64 for each theoretical plate. This data is presented in Table 7.
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p-Cymene and p-menthane are difficult to separate one from another by conventional distillation or rectification because of the close proximity of their boiling points. p-Cymene and p-menthane can be readily separated one from another by using azeotropic or extractive distillation. Typical examples of effective agents, for azeotropic distillation: diethyelene glycol ethyl ether, 1-pentanol and isobutanol; for extractive distillation: butyl benzoate, undecyl alcohol and methyl benzoate.
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FIELD OF THE INVENTION
[0001] This invention provides a novel method of producing animals, preferably agricultural animals, stem cell lines and endangered animals, by using a combination of nuclear transfer and embryonic stem cell techniques.
BACKGROUND
[0002] The field of this invention is agriculture, more specifically animal agriculture and a means of improving the quality and reliability of the breeding and growing industry. At present farm animals, including, but not limited to poultry, pigs, and cattle, are produced by breeding from select breeding stock. This invention describes a means of capturing the genotype of superior animals by NT, and producing ES cells that can be easily cryopreserved and subsequently used to produce the final cloned animal for human consumption.
[0003] 1. Nuclear Transfer
[0004] The first successful transfer of a nucleus from an adult mammary gland cell into an enucleated oocyte was reported in 1996 (Campbell et al., Nature 380: 64-6 (1996)). Nuclear transfer (NT) involves preparing a cytoplast as a recipient cell. In most cases, the cytoplast is derived from a mature metaphase II oocyte, from which the chromosomes have been removed. A donor cell nucleus is then placed between the zona and the cytoplast. Fusion and cytoplast activation are initiated by electrical stimulation. Successful reprogramming of the donor cell nucleus by the cytoplast is critical, and is a step which may be influenced by cell cycle (Wolf et al., Biol. Reprod. 60: 199-204 (1999)).
[0005] A number of pregnancies have been established using fetal cells as the source of donor nuclei. However, animal cloning is facilitated by the use of cell lines to create transgenic animals, which allow for the genetic manipulation of the cells in vitro before nuclear transfer. Id. The mechanisms regulating early embryonic development may be conserved among mammalian species, such that, for example, a bovine oocyte cytoplasm can support the introduced, differentiated, donor nucleus regardless of chromosome number, species or age of the donor fibroblast (Dominko et al., Biol. Reprod. 60: 1496-1502 (1999)).
[0006] Actively dividing fetal fibroblasts can be used as nuclear donors according to the procedure described in Cibelli et al., Science 280: 1256-9 (1998). Additional methods of preparing recipient oocytes for nuclear transfer of donor differentiated nuclei can be performed as described in International PCT Application Nos. 99/05266; 99/01164; 99/01163; 98/3916; 98/30683; 97/41209; 97/07668; 97/07669; and U.S. Pat. No. 5,843,754. Typically the transplanted nuclei are obtained from cultured embryonic stem (ES) cells, embryonic germ (EG) cells or other embryonic cells (See, e.g., International PCT Applications Nos. 95/17500 and 95/10599. Canadian Patent No. 2,092,258; Great Britain Patent No. 2.265.909; and U.S. Pat. Nos. 5,453,366; 5,057,420; 4,994,384; and 4,664,097). Inner cell mass (ICM) cells can also be used as nuclear donors (Sims et al., Proc. Natl. Acad. Sci. USA 90: 6143-7 (1990); and Keefer et al., Biol. Reprod. 50: 935-9 (1994).
[0007] II. Preparing Somatic Cells for Nuclear Transplantation or Nuclear Transfer
[0008] For purposes of animal husbandry, nuclear transfer can be used with embryonic stem cells (ES), inner cell mass cells (ICMs) and somatic cells.
[0009] Embryonic Stem Cells. Another system for producing transgenic animals has been developed that uses ES cells. In mice, ES cells have enabled researchers to select for transgenic cells and perform gene targeting. This method allows more genetic engineering than is possible with other transgenic techniques. For example, ES cells are relatively easy to grow as colonies in vitro, can be transfected by standard procedures, and the transgenic cells clonally selected by antibiotic resistance (Doetschman, “Gene transfer in embryonic stem cells.” IN TRANSGENIC ANIMAL TECHNOLOGY: A LABORATORY HANDBOOK 115-146 (C. Pinkert, ed., Academic Press. Inc., New York 1994)). Furthermore, the efficiency of this process is such that sufficient transgenic colonies (hundreds to thousands) can be produced to allow a second selection for homologous recombinants (Id.). ES cells can then be combined with a normal host embryo and, because they retain their potency, can develop into all the tissues in the resulting chimeric animal, including the germ cells. Thus, the transgenic modification is transmissible to subsequent generations.
[0010] Methods for deriving embryonic stem (ES) cell lines in vitro from early preimplantation mouse embryos are well known (Evans et al., Nature 29: 154-6 (1981); and Martin, Proc. Natl. Acad. Sci. USA 78: 7634-8 (1981)). ES cells can be passaged in an undifferentiated stale, provided that a feeder layer of fibroblast cells (Evans et al. 1981) or a differentiation inhibiting source (Smith et al., Dev. Biol. 121: 1-9 (1987)), is present.
[0011] In view of their ability to transfer their genome to the next generation, ES cells have potential utility for germ line manipulation of livestock animals. Some research groups have reported the isolation of pluripotent embryonic cell lines. For example, Notarianni et al., J. Reprod. Fert. Suppl. 43: 55-260 (1991) reported the establishment of stable, pluripotent cell lines from pig and sheep blastocysts, which exhibit some morphological and growth characteristics similar to that of cells in primary cultures of inner cell masses (ICMs) isolated immunosurgically from sheep blastocysts. Also, Notarianni et al., J. Reprod. Fert. Suppl. 41: 51-56 (1990) disclosed maintenance and differentiation in culture of putative pluripotent embryonic cell lines from pig blastocysts. Gerfen et al., Anim. Biotech. 6: 1-14 (1995) disclosed the isolation of embryonic cell lines from porcine blastocysts, which do not require mouse embryonic fibroblast feeder layers and reportedly differentiate into several different cell types during culture.
[0012] Further, Saito et al., Roux's Arch. Dev. Biol. 201: 134-41 (1992) reported cultured, bovine embryonic stem cell-like cell lines, which survived three passages, but were lost after the fourth passage. Handyside et al., Roux's Ach. Dev. Biol. 196: 185-90 (1987) disclosed culturing immunosurgically isolated sheep embryo ICMs under conditions that allow for the isolation of mouse ES cell lines derived from mouse ICMs.
[0013] Campbell et al., Nature 380: 64-6 (1996) reported the production of live lambs following nuclear transfer of cultured embryonic disc (ED) cells from day nine ovine embryos cultured under conditions which promote the isolation of ES cell lines in the mouse.
[0014] Purportedly, animal stem cells have been isolated, selected and propagated for use in obtaining transgenic animals (see Evans et al., WO 90/03432; Smith et al., WO 94/24274: and Wheeler et al., WO 94/26884). Evans et al., also reported the derivation of purportedly pluripotent ES cells from porcine and bovine species, which purportedly are useful for the production of transgenic animals.
[0015] ES cells from a transgenic embryo can be used in nuclear transplantation. The use of ungulate ICM cells for nuclear trans-plantation also has been reported. In the case of live-stock animals (e.g. ungulates) nuclei from similar preimplantation livestock embryos support the development of enucleated oocytes to term (Keefer el a). Biol. Reprod. 50: 935-39 (1994); Smith et al., Biol. Reprod. 40: 1027-1035 (1989)). In contrast, nuclei from mouse embryos do not support development of enucleated oocytes beyond the eight-cell stage after transfer (Cheong et al., Biol. Reprod. 48: 958-63 (1993)). Therefore. ES cells from livestock animals are highly desirable, because they may provide a potential source of totipotent donor nuclei, genetically manipulated or other-wise, for nuclear transfer procedures.
[0016] Use of ICM Cells. Collas et al., Mol. Reprod. Dev. 38: 264-7 (1994) disclosed nuclear transplantation of bovine ICMs by microinjection of the lysed donor cells into enucleated mature oocytes. Culturing of embryos in vitro for seven days produced fifteen blastocysts which, upon transfer into bovine recipients, resulted in four pregnancies and two births. Also, Keefer et al. (1994) disclosed the use of bovine ICM cells as donor nuclei in nuclear transfer procedures, to produce blastocysts which also resulted in several live offspring. Further, Sims et al., Proc. Natl. Acad. Sci. USA 90: 6143-7 (1993) disclosed the production of calves by transfer of nuclei from short-term in vitro cultured bovine ICM cells into enucleated mature oocytes.
[0017] Therefore, notwithstanding what has previously been reported in the literature, there exists a need for improved methods of obtaining transgenic animals by faster more cost effective means. The invention also provides for methods of making such animals and embryonic stem cell lines.
SUMMARY OF THE INVENTION
[0018] It is an object of the invention to provide an animal produced from embryonic stem cells. Where such embryonic stem cells original from a cloned embryo. The animal can be a mammal or an avian, and preferably a farm animal. Other animals contemplated for production by the methods disclosed include: bovines, non-human primates, ovines, murines, porcines, canines, felines, or caprines.
[0019] It is a further objection of the invention to provide ES cells produced from an embryo made by nuclear transfer.
[0020] Another objection of the invention provides for a business model whereby cryopreserved clonal ES cells are marketed instead of live animals for the production of farm animals.
[0021] Still a further object of the invention provides for a method for producing an embryonic stem (ES) derived cloned mammal comprising the following steps: (i) isolating a somatic cell from an animal having desired characteristic(s); (ii) transfecting such cell with a marker that allows for cells containing to be selected by positive selection; (iii) using said transfected cell as a cell or nuclear donor during a nuclear procedure; (iv) culturing the resultant nuclear transfer embryo under conditions that result into development into a blastocyst or post-blastocyst stage embryo. (v) isolating totipotent (e.g. inner cell mass cells) from said embryo and expanding said cells in culture to produce ES cells; (vi) optionally cryopreserving said expanded ES cells; (vii) inserting said ES cells into a host embryo of 1 to 200 cells which is not resistant to the selectable marker; (viii) culturing the resultant embryo under selective conditions for the selectable marker to obtain embryos that substantially consist of cells that comprise genome of ES cells; and (ix) after embryos have reached desired size transferring said embryo to a recipient female.
[0022] Also disclosed is A method for deriving a cloned animal from an ES cell comprising: (i) isolating a somatic cell from an animal having desired characteristics; (ii) using said cell as a cell or nuclear donor during nuclear transfer; (iii) using the resultant nuclear transfer fusion to produce an embryo of the blastocyst stage or later; (iv) isolating totipotent cells (e.g., inner cell mass cells) from said embryo and expanding said cells in culture to produce ES cells; (v) optionally cryopreserving said ES cells; (vi) inserting some of said ES cells into a host embryo of 2 to 200 cells which is incapable of development; (vii) culturing the resultant embryo until it is of a size suitable for implantation into a recipient female; (viii) transferring said cultured embryo into a recipient female.
[0023] Another object of the invention is to provide for a method for producing an avian from ES cells comprising: (i) isolating ES cells from an avian having desired characteristics; (ii) expanding said ES cells in culture and optionally cryopreserving said expanded ES cells; (iii) obtaining eggs that are unable to develop into an embryo; (iv) injecting said eggs with said ES cells: and (g) incubating said eggs to produce avian offspring having the genotype of ES cells. Preferred avian species include: chicken, turkey, guinea hen, ostrich, eagle, osprey, condor, bird of prey, or avian near extinction.
[0024] Another object of the invention is to provide for animals and ES cells in which one or more genes have been genetically introduced, deleted or otherwise modified.
BRIEF DESCRIPTION OF THE FIGURES
[0025] [0025]FIG. 1. Generation of transgenic ES-like cells. FIG. 1A: Embryo-derived ES-like cells. FIG. 1B. β-galactosidase activity of transgenic embryo-derived ES-like cells. FIG. 1C. β-galactosidase activity of transgenic fetal fibroblasts. FIG. 1D. Nuclear transfer-derived ES-like cells. PCR ethidium bromide gel of β-galactosidase fragment. Lane 1: non-transgenic embryo-derived ES-like cells lane 2: transgenic embryo-derived ES-like cells; lane 3: transgenic fetal fibroblasts lane 4: transgenic nuclear transfer-derived ES-like cells; lane 5: non-transgenic fetal fibroblasts; lane 8: template.
[0026] [0026]FIG. 2. Generation of transgenic ES-like cells (A) by microinjection and (B) by somatic cell nuclear transfer.
[0027] [0027]FIG. 3. Southern blot analysis of PCR-amplified products of tissues from chimeric calves. Calves 901 and 903 were generated from embryo-derived ES-like transgenic cells. Calves 907 and 912 were generated from nuclear transfer-derived ES-like transgenic cells.
[0028] [0028]FIG. 4. FISH analysis of spleen from calf 911 (FIG. 1A) produced with NT-derived ES-like cells, negative control spleen (FIG. 1B), testis of calf 903 produced with embryo-derived ES-like cells (FIG. 1C), and negative control testis (FIG. 1D).
BRIEF DESCRIPTION OF THE INVENTION
[0029] The current technologies used to deliver optimized farm animals are based on selective breeding, and expansion from preferred breeding stocks. Animals that have been selected on the basis of superior characteristics, such as meal content, egg production (in the case of poultry), feed conversion ratio and so on are used to breed large numbers of animals that are in turn used in the human food supply. This traditional process has profound inherent inefficiencies. The phenotype observed in an individual animal is often only partially transmitted in the progeny of that animal. Therefore, traditional breeding schemes are inefficient in capturing the very best phenotype in all of the progeny animals. In addition, in some cases, such as in poultry breeding, the breeding stock need to be prepared months in advance of actual sale, and the demand at the end of the breeding process may be far above or below the numbers of animals actually produced. Therefore the breeder may experience large losses from overproduction or lost sales from underproduction that cannot be adequately controlled. This invention allows the production of the final animal from cloned embryonic stem cells that have the ideal phenotype and can be easily cryopreserved and thawed to meet the needs of the grower. In addition, embryonic stem cells possess replicative immortality facilitating the modification of the genome by gene targeting and other means, allowing the supplier of such cells to introduce genetic modifications into the germ line of the cloned animals to meet the needs of the marketplace.
DETAILED DESCRIPTION
[0030] 1. Definitions
[0031] By “animal” is meant to include avians, mammals, reptiles and amphibians. Preferred animals include avians and mammals as well as any animal that is an endangered species. Preferred birds include domesticated birds (e.g. quail, chickens. ducks, geese, turkeys, and guinea hens) as well as other birds such as birds of prey (e.g., hawks, falcons, ospreys, condors. etc.), endangered birds (e.g., parrots, California condor, etc.), ostriches etc. Preferred mammals include murine, caprine, ovine, bovine, porcine, canine, feline and primate. Of these, preferred members include domesticated ungulates (e.g., cattle, buffalo, pigs, sheep, and goats) and humans.
[0032] By “female surrogate” is meant a female animal into which an embryo of the invention is inserted for gestation. Typically, the female animal is of the same animal species as the embryo, but the female surrogate may also be of a different animal species. The embryo, as used herein, can include a complex of two or more cells.
[0033] By “cytoplast” is meant the fragment of the cell remaining once the nucleus is removed.
[0034] By “enucleated oocyte” is meant an animal egg which has had its endogenous nucleus removed or inactivated.
[0035] By “sperm” “semen,” “sperm sample,” and “semen sample” are meant the ejaculate from a male animal which contains spermatozoa. A mature sperm cell is a “spermatozoon,” whereas the precursor is a “spermatid.” Spermatids are the haploid products of the second meiotic division in spermatogenesis, which differentiate into spermatozoa.
[0036] The terms “nuclear transfer” or “nuclear transplantation” refer to a method of cloning, wherein the donor cell nucleus is transplanted into a cell before or after removal of its endogenous nucleus. The cytoplast could be from an enucleated oocyte, an enucleated ES cell, an enucleated EG cell, an enucleated embryonic cell or an enucleated somatic cell. Nuclear transfer techniques or nuclear transplantation techniques are known in the literature (Campbell et al., Theriogenology 43: 181 (1995); Collas et al., Mol. Reprod. Dev. 38: 264-267 (1994); Keefer et al., Biol. Reprod. 50: 935-939 (1994); Sims et al., Proc. Natl. Acad. Sci. USA 90: 6143-6147 (1993); Evans et al., WO 90/03432; Smith et al., WO 94/24274; and Wheeler et al., WO 94/26884. Also U.S. Pat. Nos. 4,994,384 and 5,057,420 describe procedures for bovine nuclear transplantation. In the subject application, “nuclear transfer” or “nuclear transplantation” or “NT” are used interchangeably.
[0037] The terms “nuclear transfer unit” and “NT unit” refer to the product of fusion between or injection of a somatic cell or cell nucleus and an enucleated cytoplast (e.g., an enucleated oocyte), which is some-times referred to herein as a fused NT unit.
[0038] By “somatic cell” is meant any cell of a multicellular organism, preferably an animal, that does not become a gamete.
[0039] By “differentiate” or “differentiation” is meant to refer to the process in development of an organism by which cells become specialized for particular functions. Differentiation requires that there is selective expression of portions of the genome.
[0040] By, “inner cell mass” or “ICM” is meant a group of cells found in the mammalian blastocyst that give rise to the embryo and are potentially capable of forming all tissues, embryonic and extra-embryonic, except the trophoblast.
[0041] By “feeder layer” is meant a layer of cells to condition the medium in order to culture other cells, particularly to culture those cells at low or clonal density.
[0042] By “medium” or “media” is meant the nutrient solution in which cells and tissues are grown.
[0043] II. Production of ES-Derived Cloned Mammals:
[0044] The Steps used are:
[0045] 1) Isolate a somatic cell from an optimal animal
[0046] 2) Tranfect such cells with an antibiotic resistance gene or any other gene that would allow the selection of these cells by positive selection. An example would be the use of the neomycin resistance gene.
[0047] 3) Take one of these cells and perform nuclear transfer to be able to have ES cells from the somatic cells.
[0048] 4) Cryopreserve large quantities of ampules of the ES cells.
[0049] 5) Take some of these ES cells between 2 to 20, preferably 12 and inject them into a host mammalian embryo. Such embryo should be in the stage between one to 200 cells preferably between 8 to 16 cells. The host embryo should not be resistant to the previously-mentioned selectable marker gene.
[0050] 6) Place the embryos is culture with a specific dosage of the selection substance, in the example of the neomycin resistance gene. G418.
[0051] 7) After 7 days in culture, embryos are transferred into the recipient females.
[0052] III. An Alternative Method for the Production of ES-Derived Cloned Mammals
[0053] The Steps used are:
[0054] 1) Isolate a somatic cell from an optimal animal.
[0055] 2) Take one of these cells and perform nuclear transfer to be able to have ES cells from the somatic cells.
[0056] 3) Cryopreserve large quantities of ampules of the ES cells.
[0057] 4) Take some of these ES cells between 2 to 20, preferably 12 and inject them into a host mammalian embryo. Such embryo should be in the stare between one to 200 cells preferably between 8 to 16 cells. The host embryo should be incapable of development, being for example, a tetraploid embryo.
[0058] 5) After 7 days in culture, embryos are transferred into the recipient females.
[0059] IV. Production of ES-Derived Poultry
[0060] The Steps used are:
[0061] 1) Isolate ES cells from a superior breeding stock of avian species.
[0062] 2) Scale cells up and cryopreserve large quantities of ampules of cells.
[0063] 3) Recipient eggs are prepared that are deficient in embryo production by genetic modification of the laying hen, or by exogenous means such as irradiation.
[0064] 4) injection of ES cells from the genotype desired.
[0065] 5) Incubation to hatch.
[0066] 6) Growth of final broiler.
[0067] V. Genetic Modification of Animal ES Cells
[0068] The marketed avian or mammalian ES cells may subsequently be modified by gene targeting or other means of genetic modification to introduce improved genetics of the final animal.
[0069] VI. Business Marketing Model
[0070] The product envisioned is cryopreserved animal ES cells that are stable for long periods of time, and can be stored inexpensively. When the final animal is in demand, the vials can he thawed and injected into the host embryo to produce the final animal. This allows the marketing of cryovials as opposed to live animals. The business model is to market clonal ES cells to the final growers. The end customer will also be sold the injection equipment and allied supplies such as host embryos and eggs to produce the final animals.
[0071] VII. Nuclear Transfer
[0072] Preferably, the NT units used to produce ES-like cells will be cultured to a size of at least 2 to 400 cells, preferably 4 to 128 cells, and most preferably to a size of at least about 50 cells.
[0073] In the present invention, embryonic stem cells, embryonic germ cells and embryonic stem-like cells can be produced according to the present invention. The present application refers to stem-like cells rather than stem cells because of the manner in which they are typically produced. i.e. by cross-species nuclear transfer. While these cells are expected to possess similar differentiation capacity as normal stem cells they may possess some insignificant differences because of the manner they are produced. For example, these stem-like cells may possess the mitochondria of the oocytes used for nuclear transfer, and thus not behave identically to conventional embryonic stem cells.
[0074] Based on the fact that human cell nuclei can be effectively transplanted into bovine oocytes, it is reasonable to expect that human cells maybe transplanted into oocytes of other non-related species, e.g. other ungulates as well as other animals. In particular, other ungulate oocytes should be suitable, e.g., pigs, sheep, horses, goats. etc. Also, oocytes from other sources should be suitable e.g. oocytes derived from other primates, amphibians, rodents, rabbits, guinea pigs, etc. Further, using similar methods, it should be possible to transfer human cells or cell nuclei into human oocytes and use the resultant blastocysts to produce human ES cells.
[0075] Therefore, in one embodiment, the present invention involves the transplantation of an animal or human cell nucleus or animal or human cell into an oocyte (preferably enucleated) of an animal species different from the donor nuclei, by injection or fusion. To produce an NT unit containing cells which may be used to obtain embryonic or stem-like cells and/or cell cultures. In another embodiment, a nucleus of an animal is injected or fused to an oocyte from the same animal species.
[0076] Enucleation (removal of endogenous oocyte nucleus) may be effected before or after nuclear transfer. For example, the invention may involve the transplantation of an ungulate cell nucleus or ungulate cell into an enucleated oocyte, e.g. another ungulate or non-ungulate, by injection or fusion, which cells and/or nuclei are combined to produce NT units and which are cultured under conditions suitable to obtain multicellular NT units, preferably comprising at least about 2 to 400 cells, more preferably 4 to 128 cells, and most preferably at least about 50 cells. The cells of such NT units may be used to produce EG cells, ES cells, and ES-like cells as well as cell colonies upon culturing.
[0077] Nuclear transfer techniques or nuclear transplantation techniques are known in the literature and are described in many of the references cited in the Background of the Invention. See, in particular, Campbell et al. Theriogenology, 43:181 (1995); Collas et al, Mol. Report Dev., 38:264-267 (1994); Keefer et al, Biol. Reprod., 50:935-939 (1994); Sims et al, Proc. Natl. Acad. Sci. USA, 90:6143-6147 (1993); WO 94/26884; WO 94/24274, and WO 90/03432, which are incorporated by reference in their entirety herein. Also, U.S. Pat. Nos. 4,944,384 and 5,057,420 describe procedures for bovine nuclear transplantation. See, also Cibelli et al, Science, Vol. 280:1256-1258 (1998).
[0078] Human or animal cells, preferably mammalian cells, may be obtained and cultured by well known methods. Human and animal cells useful in the present invention include, by way of example, epithelial, neural cells, epidermal cells, keratinocytes, hematopoietic cells, melanocytes, chondrocytes, lymphocytes (B and T lymphocytes), other immune cells, erythocytes, macrophages, melanocytes, monocytes, mononuclear cells, fibroblasts, cardiac muscle cells, and other muscle cells. etc. Moreover, the human cells used for nuclear transfer may be obtained from different organs. e.g. skin, lung, pancreas, liver, stomach, intestine, heart, reproductive organs, bladder, kidney, urethra and other urinary organs. etc. These are just examples of suitable donor cells. Suitable donor cells, i.e., cells useful in the subject invention, may be obtained from any cell or organ of the body. This includes all somatic or germ cells. Preferably, the donor cells or nucleus would comprise actively dividing. i.e. non-quiescent., cells as this has been reported to enhance cloning efficacy. Also preferably, such donor cells will be in the G1 cell cycle.
[0079] The resultant blastocysts may be used to obtain embryonic stem cell lines according to the culturing methods reported by Thomson et al., Science, 282:1145-1147 (1998) and Thomson et al., Proc. Natl. Acad. Sci., USA, 92:7544-7848 (1995), incorporated by reference in their entirety herein.
[0080] In the Example which follows, the cells used as donors for nuclear transfer were epithelial cells derived from the oral cavity of a human donor and adult human keratinocytes. However, as discussed, the disclosed method is applicable to other human cells or nuclei. Moreover, the cell nuclei may be obtained from both human somatic and germ cells.
[0081] It is also possible to arrest donor cells at mitosis before nuclear transfer, using a suitable technique known in the art. Methods for stopping the cell cycle at various stages have been thoroughly reviewed in U.S. Pat. No. 5,262,409, which is herein incorporated by reference. In particular, while cycloheximide has been reported to have an inhibitory effect on mitosis (Bowen and Wilson (1955) J. Heredity, 45:3-9), it may also be employed for improved activation of mature bovine follicular oocytes when combined with electric pulse treatment (Yang et al., (1992) Biol. Reprod., 42 (Suppl. 1): 117).
[0082] Zygote gene activation is associated with hyperacetylation of Histone H4. Trichostatin-A has been shown to inhibit histone deacetylase in a reversible manner (Adenot et al., Development (1997) 124(22): 4615-4625; Yoshida et al., Bioessays (1995) 17(5): 423-430), as have other compounds. For instance, butyrate is also believed to cause hyper-acetylations of histones by inhibiting histone deacetylase. Generally, butyrate appears to modify gene expression and in almost all cases its addition to cells in culture appears to arrest cell growth. Use of butyrate in this regard is described in U.S. Pat. No. 5,681,718, which is herein incorporated by reference. Thus, donor cells may be exposed to Trichostatin-A or another appropriate deacetylase inhibitor prior to fusion, or such a compound may be added to the culture media prior to genome activation.
[0083] Additionally, demethylation of DNA is thought to be a requirement for proper access of transcription factors to DNA regulatory sequences. Global demethylation of DNA from the eight-cell stage to the blastocyst stage in preimplantation embryos has previously been described (Stein et al., Mol. Reprod. & Dev., 47(4): 421-429). Also, Jaenisch et al. (1997) have reported that 5-azacytidine can be used to reduce the level of DNA methylation in cells, potentially leading to increased access of transcription factors to DNA regulatory sequences. Accordingly, donor cells may be exposed to 5-azacytidine (5-Aza) previous to fusion, or 5-Aza may be added to the culture medium from the 8 cell stage to blastocyst. Alternatively, other known methods for effecting DNA demethylation may be used.
[0084] The oocytes used for nuclear transfer may be obtained from animals including mammals, avians, reptiles, and amphibians. Suitable mammalian sources for oocytes include sheep, bovines, ovines, pigs, horses, rabbits, goats, guinea pigs, mice, hamsters, rats, primates, humans, etc. In the preferred embodiments, the oocytes will be obtained from primates or ungulates, e.g., a bovine.
[0085] Methods for isolation of oocytes are well known in the art. Essentially, this will comprise isolating oocytes from the ovaries or reproductive tract of a mammal or amphibian, e.g., a bovine. A readily available source of bovine oocytes is slaughterhouse materials.
[0086] For the successful use of techniques such as genetic engineering, nuclear transfer and cloning, oocytes must generally be matured in vitro before these cells may be used as recipient cells for nuclear transfer, and before they can be fertilized by the sperm cell to develop into an embryo. This process generally requires collecting immature (prophase I) oocytes from animal ovaries. e.g. bovine ovaries obtained at a slaughterhouse and maturing the oocytes in a maturation medium prior to fertilization or enucleation until the oocytes attains the metaphase II stage, which in the case of bovine oocytes generally occurs about 18-24 hours post-aspiration. For purposes of the present invention, this period of time is known as the “maturation period.” As used herein for calculation of time periods. “aspiration” refers to aspiration of the immature oocyte from ovarian follicles.
[0087] Additionally, metaphase II stage oocytes, which have been matured in vivo have been successfully used in nuclear transfer techniques. Essentially, mature meta-phase II oocytes are collected surgically from either non-superovulated or superovulated cows or heifers 35 to 48 hours past the onset of estrus or past the injection of human chorionic gonadotropin (hCG) or similar hormone.
[0088] The stage of maturation of the oocyte at enucleation and nuclear transfer has been reported to be significant to the success of NT methods. (See, e.g., Prather et al., Differentiation: 48: 1-8, 1991). In general, previous successful mammalian embryo cloning practices used metaphase II stage oocyte as the recipient oocyte because at this stage it is believed that the oocyte can be or is sufficiently “activated” to treat the introduced nucleus as it does a fertilizing sperm. In domestic animals, and especially cattle, the oocyte activation period generally ranges from about 16-52 hours, preferably about 28-42 hours post-aspiration.
[0089] For example, immature oocytes may be washed in HEPES buffered hamster embryo culture medium (HECM) as described in Seshagine et al., Biol. Reprod., 40: 544-606 (1989) and then placed into drops of maturation medium consisting of 50 μl of tissue culture medium (TCM) 199 containing 10% fetal calf serum which contains appropriate gonadotropins such as luteinizing hormone (LH) and follicle stimulating hormone (FSH), and estradiol under a layer of lightweight paraffin or silicon at 39° C.
[0090] After a fixed time maturation period, which typically will range from about 10 to 40 hours, and preferably about 16-18 hours, the oocytes will typically be enucleated. Prior to enucleation the oocytes will preferably be removed and placed in HECM containing 1 mg/ml of hyaluronidase prior to removal of cumulus cells. This may be effected by repeated pipetting through very fine bore pipettes or by vortexing briefly. The stripped oocytes are then screened for polar bodies, and the selected metaphase II oocytes, as determined by the presence of polar bodies, are then used for nuclear transfer. Enucleation follows. As noted above, enucleation may be effected before or after introduction of donor cell or nucleus because the donor nucleus is readily discernible from endogenous nucleus.
[0091] Enucleation may be effected by known methods, such as described in U.S. Pat. No. 4,994,384 which is incorporated by reference herein. For example, metaphase II oocytes are either placed in HECM, optionally containing 7.5 μg/ml cytochalasin B, for immediate enucleation, or may be placed in a suitable medium, for example CR1aa, plus 10% estrus cow serum, and then enucleated later, preferably not more than 24 hours later, and more preferably 16-18 hours later.
[0092] Enucleation may be accomplished microsurgically using a micropipette to remove the polar body and the adjacent cytoplasm. The oocytes may then be screened to identify, those of which have been successfully enucleated. This screening may be effected by staining the oocytes with 1 μg/ml 33342 Hoechst dye in HECM, and then viewing the oocytes under ultraviolet irradiation for less than 10 seconds. The oocytes that have been successfully enucleated can then be placed in a suitable culture medium.
[0093] In the present invention, the recipient oocytes will typically be enucleated at a time ranging from about 10 hours to about 40 hours after the initiation of in vitro maturation, more preferably from about 16 hours to about 24 hours after initiation of in vitro maturation, and most preferably about 16-18 hours after initiation of in vitro maturation. Enucleation may be effected before, simultaneous or after nuclear transfer. Also, enucleation may be effected before, after or simultaneous to activation.
[0094] A single animal or human cell or nucleus derived therefrom which is typically heterologous to the enucleated oocyte will then be transferred into the perivitelline space of the oocyte, typically enucleated, used to produce the NT unit. However, removal of endogenous nucleus may alternatively be effected after nuclear transfer. The animal or human cell or nucleus and the enucleated oocyte will be used to produce NT units according to methods known in the art. For example, the cells may be fused by electrofusion. Electrofusion is accomplished by providing a pulse of electricity that is sufficient to cause a transient break down of the plasma membrane. This breakdown of the plasma membrane is ver, short because the membrane reforms rapidly. Essentially, if two adjacent membranes are induced to break down, upon reformation the lipid bilayers intermingle and small channels will open between the two cells. Due to the thermodynamic instability of such a small opening, it enlarges until the two cells become one. Reference is made to U.S. Pat. No. 4,997,384, by Prather et a)., (incorporated by reference in its entirety herein) for a further discussion of this process. A variety of electrofusion media can be used including, e.g., sucrose, mannitol, sorbitol and phosphate buffered solution. Fusion can also be accomplished using Sendai virus as a fusogenic agent (Graham, Wister Inot. Symp. Monogr., 9:19, 1969).
[0095] Also, in some cases (e.g. with small donor nuclei) it may be preferable to inject the nucleus directly into the oocyte rather than using electroporation fusion. Such techniques are disclosed in Collas and Barnes, Mol. Reprod. Dev., 38: 264-7 (1994), and incorporated by reference in its entirety herein.
[0096] Preferably, the human or animal cell and oocyte are electrofused in a 500 μm chamber by application of an electrical pulse of 90-120V for about 15 μsec, about 24 hours after initiation of oocyte maturation. After fusion, the resultant fused NT units are preferably placed in a suitable medium until activation. e.g. one identified infra. Typically activation will be effected shortly thereafter, typically less than 24 hours later, and preferably about 4-9 hours later. However, it is also possible to activate the recipient oocyte before or proximate (simultaneous) to nuclear transfer, which may or may not be enucleated. For example, activation may be effected from about twelve hours prior to nuclear transfer to about twenty-four hours after nuclear transfer. More typically, activation is effected simultaneous or shortly after nuclear transfer, e.g., about four to nine hours later.
[0097] The NT unit may be activated by known methods. Such methods include, e.g., culturing the NT unit at sub-physiological temperature, in essence by applying a cold, or actually cool temperature shock to the NT unit. This may be most conveniently done by culturing the NT unit at room temperature, which is cold relative to the physiological temperature conditions to which embryos are normally exposed.
[0098] Alternatively, activation may be achieved by application of known activation agents. For example, penetration of oocytes by sperm during fertilization has been shown to activate prefusion oocytes to yield greater numbers of viable pregnancies and multiple genetically identical calves after nuclear transfer. Also, treatments such as electrical and chemical shock or cycloheximide treatment may also be used to activate NT embryos after fusion. Suitable oocyte activation methods are the subject of U.S. Pat. No. 5,496,720, to Susko-Parrish et al. which is herein incorporated by reference.
[0099] For example, oocyte activation may be effected by simultaneously or sequentially:
[0100] (i) increasing levels of divalent cations in the oocyte, and
[0101] (ii) reducing phosphorylation of cellular proteins in the oocyte.
[0102] This will generally be effected by introducing divalent cations into the oocyte cytoplasm, e.g., magnesium, strontium, barium or calcium, e.g., in the form of an ionophore. Other methods of increasing divalent cation levels include the use of electric shock, treatment with ethanol and treatment with caged chelators.
[0103] Phosphorylation may be reduced by known methods, e.g. by the addition of kinase inhibitors, e.g., serine-threonine kinase inhibitors, such as 6-dimethylamino-purine, staurosporine, 2-aminopurine, and sphingosine.
[0104] Alternatively, phosphorylation of cellular proteins may be inhibited by introduction of a phosphatase into the oocyte, e.g., phosphatase 2A and phosphatase 2B.
[0105] Specific examples of activation methods are listed below.
[0106] 1. Activation by Ionomycin and DMAP
[0107] 1—Place oocytes in Ionomycin (5 μM) with 2 mM of DMAP for 4 minutes;
[0108] 2—Move the oocytes into culture media with 2 mM of DMAP for 4 hours;
[0109] 3—Rinse four times and place in culture.
[0110] 2. Activation by Ionomycin DMAP and Roscovitin
[0111] 1—Place oocytes in Ionomycin (5 μM) with 2 mM of DMAP for four minutes;
[0112] 2—Move the oocytes into culture media with 2 mM of DMAP and 200 microM of Roscovitin for three hours.
[0113] 3—Rinse four times and place in culture.
[0114] 3. Activation by exposure to Ionomycin followed by cytochalasin and cycloheximide.
[0115] 1—Place oocytes in Ionomycin (5 microM) for four minutes;
[0116] 2—Move oocytes to culture media containing 5 μg/ml of cytochalasin B and 5 μg/ml of cycloheximide for five hours;
[0117] 3—Rinse four times and place in culture.
[0118] 4. Activation by electrical pulses
[0119] 1—Place eggs in mannitol media containing 100 μM CaCL 2 ;
[0120] 2—Deliver three pulses of 1.0 kVcm −1 for 20 μsec. each pulse 22 minutes apart;
[0121] 3—Move oocytes to culture media containing 5 μg/ml of cytochalasin B for three hours.
[0122] 5. Activation by exposure with ethanol followed by cytochalasin and cycloheximide
[0123] 1—Place oocytes in 7% ethanol for one minute;
[0124] 2—Move oocytes to culture media containing 5 μg/ml of cytochalasin B and 5 μg/ml of cycloheximide for five hours;
[0125] 3—Rinse four times and place in culture.
[0126] 6. Activation by microinjection of adenophostine
[0127] 1—Inject oocytes with 10 to 12 picoliters of a solution containing 10 μM of adenophostine;
[0128] 2—Put oocytes in culture.
[0129] 7. Activation by microinjection of sperm factor
[0130] 1—Inject oocytes with 10 to 12 picoliters of sperm factor isolated, e.g., from primates, pigs, bovine, sheep, goals, horses, mice, rats, rabbits or hamsters.
[0131] 2—Put eggs in culture.
[0132] 8. Activation by microinjection of recombinant sperm factor.
[0133] 9. Activation by Exposure to DMAP followed by Cycloheximide and Cytochalasin B
[0134] Place oocytes or NT units, typically about 22 to 28 hours post maturation in about 2 mM DMAP for about one hour, followed by incubation for about two to twelve hours, preferably about eight hours, in 5 μg/ml of cytochalasin B and 20 μg/ml cycloheximide.
[0135] The above activation protocols are exemplary of protocols used for nuclear transfer procedures, e.g., those including the use of primate or human donor cells or oocytes. However, the above activation protocols may be used when either or both the donor cell and nucleus is of ungulate origin, e.g., a sheep, buffalo, horse, goat, bovine, pig and/or wherein the oocyte is of ungulate origin, e.g. sheet, pig, buffalo, horse, goal, bovine, etc., as well as for other species.
[0136] As noted, activation may be effected before, simultaneous, or after nuclear transfer. An general, activation will be effected about 40 hours prior to nuclear transfer and fusion to about 40 hours after nuclear transfer and fusion, more preferably about 24 hours before 10 about 24 hours after nuclear transfer and fusion, and most preferably from about 4 to 9 hours before nuclear transfer and fusion to about 4 to 9 hours after nuclear transfer and fusion. Activation is preferably effected after or proximate to in vitro or in vivo maturation of the oocyte, e.g., approximately simultaneous or within about 40 hours of maturation, more preferably within about 24 hours of maturation.
[0137] Activated NT units may be cultured in a suitable in vitro culture medium until the generation of embryonic or stem-like cells and cell colonies. Culture media suitable for culturing and maturation of embryos are well known in the art. Examples of known media, which may be used for bovine embryo culture and maintenance. include Ham's F-10 supplemented with 10% fetal calf serum (FCS), Tissue Culture Medium-199 (TCM-199) supplemented with 10% fetal calf serum. Tyrodes-Albumin-Lactate-Pyruvate (TALP), Dulbecco's Phosphate Buffered Saline (PBS), Eagle's and Whitten's media. One of the most common media used for the collection and maturation of oocytes is TCM-199, and 1 to 20% serum supplement including fetal calf serum, newborn serum, estrual cow serum, lamb serum or steer serum. A preferred maintenance medium includes TCM-199 with Earl salts, 10% fetal calf serum, 0.2 M pyruvate and 50 μg/ml gentamycin sulphate. Any of the above may also involve co-culture with a variety of cell types such as granulosa cells oviduct cells. BRL cells and uterine cells and STO cells.
[0138] In particular, human epithelial cells of the endometrium secrete leukemia inhibitory factor (LIF) during the preimplantation and implantation period. Therefore, the addition of LIF to the culture medium could be of importance in enhancing the in vitro development of the reconstructed embryos. The use of LIF for embryonic or stem-like cell cultures has been described in U.S. Pat. No. 5,712,156, which is herein incorporated by reference.
[0139] Another maintenance medium is described in U.S. Pat. No. 5,096,822 to Rosenkrans, Jr. et al., which is incorporated herein by reference. This embryo medium, named CR1, contains the nutritional substances necessary to support an embryo. CR1 contains hemicalcium L-lactate in amounts ranging from 1.0 mM to 10 mM, preferably 1.0 mM to 5.0 mM. Hemicalcium L-lactate is L-lactate with a hemicalcium salt incorporated thereon.
[0140] Also, suitable culture medium for maintaining human embryonic cells in culture as discussed in Thomson et al., Science, 282:1145-7 (1998) and Proc. Natl. Acad. Sci. USA, 92: 7844-8 (1995).
[0141] Afterward, the cultured NT unit or units are preferably washed and then placed in a suitable media, e.g., CR1aa medium. Ham's F-10, Tissue Culture Media-199 (TCM-199). Tyrodes-Albumin-Lactate-Pyruvate (TALP) Dulbecco's Phosphate Buffered Saline (PBS), Eagle's or Whitten's, preferably containing about 10% FCS. Such culturing will preferably be effected in well plates which contain a suitable confluent feeder layer. Suitable feeder layers include, by way of example, fibroblasts and epithelial cells e.g. fibroblasts and uterine epithelial cells derived from ungulates, chicken fibroblasts murine (e.g. mouse or rat) fibroblasts. STO and S1-m220 feeder cell lines, and BRL cells.
[0142] In the preferred embodiment, the feeder cells will comprise mouse embryonic fibroblasts. Means for preparation of a suitable fibroblast feeder layer are described in the example which follows and is well within the skill of the ordinary artisan.
[0143] The NT units are cultured on the feeder layer until the NT units reach a size suitable for obtaining cells which may be used to produce embryonic stem-lire cells or cell colonies. Preferably, these N units will be cultured until they reach a size of at least about 2 to 400 cells, more preferably about 4 to 128 cells, and most preferably at least about 50 cells. The culturing will be effected under suitable conditions. i.e. about 38.5° C. and 5% CO 2 with the culture medium changed in order to optimize growth typically about every 2-5 days, preferably about every 3 days.
[0144] In the case of human cell/enucleated bovine oocyte derived NT units, sufficient cells to produce an ES cell colony, typically on the order of about 50 cells, will be obtained about 12 days after initiation of oocyte activation. However, this may vary dependent upon the particular cell used as the nuclear donor, the species of the particular oocyte, and culturing conditions. One skilled in the an can readily ascertain visually when a desired sufficient number of cells has been obtained based on the morphology of the cultured NT units.
[0145] In the case of human/human nuclear transfer embryos, or other embryos produced using non-human primate donor or oocyte, it maybe advantageous to use culture medium known to be useful for maintaining human and other primate cells in tissue culture. Examples of a culture media suitable for human embryo culture include the medium reported in Jones et al., Human Reprod., 13(1): 169-177 (1998), the P1-catalog #99242 medium, and the P-1 catalog #99292 medium, both available from Irvine Scientific. Santa Ana, Calif. and those used by Thomson et al., (1998) and (1995), which references are incorporated by reference in their entirety.
[0146] Another preferred medium comprises: ACM, uridine, glucose, 1000 IU of LIF.
[0147] As discussed above, the cells used in the present invention will preferably comprise mammalian somatic cells., most preferably cells derived from an actively proliferating (non-quiescent) mammalian cell culture. In an especially preferred embodiment, the donor cell will be genetically modified by the addition, deletion or substitution of a desired DNA sequence. For example, the donor cell. e.g. a keratinocyte or fibroblast. e.g. of human, primate or bovine origin, may be transfected or transformed with a DNA construct that provides for the expression of a desired gene product, e.g., therapeutic polypeptide. Examples thereof include lymphokines, e.g., IGF-I, IGF-II, interferons, colony stimulating factors, connective tissue polypeptides such as collagens, genetic factors, clotting factors, enzymes, enzyme inhibitors. etc.
[0148] Also, as discussed above, the donor cells may be modified prior to nuclear transfer, e.g. to effect impaired cell lineage development, enhanced embryonic development and/or inhibition of apoptosis. Examples of desirable modifications are discussed further below.
[0149] One aspect of the invention will involve genetic modification of the donor cell. e.g., a human cell, such that it is lineage deficient and therefore hen used for nuclear transfer it will be unable to give rise to a viable offspring. This is desirable especially in the context of human nuclear transfer embryos, wherein for ethical reasons, production of a viable embryo may be an unwanted outcome. This can be effected by genetically engineering a human cell such that it is incapable of differentiating into specific cell lineages when used for nuclear transfer. In particular, cells may be genetically modified such that when used as nuclear transfer donors the resultant “embryos” do not contain or substantially lack at least one of mesoderm, endoderm or ectoderm tissue.
[0150] This can be accomplished by. e.g. knocking-out or impairing the expression of one or more mesoderm, endoderm or endoderm specific genes. Examples thereof include:
[0151] Mesoderm: SRF, MESP-1, HNF-4, beta-I integrin, MSD;
[0152] Endoderm: GATA-6, GATA-4;
[0153] Ectoderm: RNA helicase A, H beta 58.
[0154] The above list is intended to be exemplar and non-exhaustive of known genes which are involved in the development of mesoderm, endoderm and ectoderm. The generation of mesoderm deficient, endoderm deficient and ectoderm deficient cells and embryos has been previously reported in the literature. See, e.g. Arsenian et al., EMBO J., 17(2): 6289-99 (1998); Saga. Mech. Dev., 75(1-2): 53-66 (1998). Holdener et al. Development. 120(5): 1355-1346 (1994); Chen et al., Genes Dev. 8(20): 2466-77 (1994): Rohwedel et al. Dev. Biol., 201(2): 167-89 (1998) (mesoderm); Morrisey et al. Genes. Dev. 12(22): 3579-90 (1998); Soudais et al. Development, 121(11):3877-88 (1995) (endoderm); and Lee et al., Proc. Natl. Acad. Sci. USA, 95(23): 13709-13 (1998); and Radice et al., Development. 111(3): 801-11 (1991) (ectoderm).
[0155] In general, a desired somatic cell. e.g. a human keratinocyte, epithelial cell or fibroblast, will be genetically engineered such that one or more genes specific to particular cell lineages are “knocked-out” and/or the expression of such genes significantly impair ed. This may be effected by known methods, e.g. homologous recombination. A preferred genetic system for effecting “knock-out” of desired genes is disclosed by Capecchi et al., U.S. Pat. Nos. 5,631,153 and 5,464,764, which reports positive-negative selection (PNS) vectors that enable targeted modification of DNA sequences in a desired mammalian genome. Such genetic modification will result in a cell that is incapable of differentiating into a particular cell lineage when used as a nuclear transfer donor.
[0156] This genetically modified cell will be used to produce a lineage-defective nuclear transfer embryo. i.e., that does not develop at least one of a functional mesoderm, endoderm or ectoderm. Thereby, the resultant embryos, even if implanted, e.g., into a human uterus, would not give rise to a viable offspring. However, the ES cells that result from such nuclear transfer will still be useful in that they will produce cells of the one or two remaining non-impaired lineage. For example, an ectoderm deficient human nuclear transfer embryo will still give rise to mesoderm and endoderm derived differentiated cells. An ectoderm deficient cell can be produced by deletion and/or impairment of one or both of RNA helicase A or H beta 58 genes.
[0157] These lineage deficient donor cells may also be genetically modified to express another desired DNA sequence.
[0158] Thus, the genetically modified donor cell will give rise to a lineage-deficient blastocyst which, when plated, will differentiate into at most two of the embryonic germ layers.
[0159] Alternatively, the donor cell can be modified such that it is “mortal.” This can be achieved by expressing antisense or ribozyme telomerase genes. This can be effected by known genetic methods that will provide for expression of antisense DNA or ribozymes, or by gene knockout. These “mortal” cells, when used for nuclear transfer, will not be capable of differentiating into viable offspring.
[0160] Another preferred embodiment of the present invention is the production of nuclear transfer embryos that grow more efficiently in tissue culture. This is advantageous in that it should reduce the requisite time and necessary fusions to produce ES cells and/or offspring (if the blastocysts are to be implanted into a female surrogate). This is desirable also because it has been observed that blastocysts and ES cells resulting from nuclear transfer may have impaired development potential. While these problems may often be alleviated by alteration of tissue culture conditions, an alternative solution is to enhance embryonic development by enhancing expression of genes involved in embryonic development.
[0161] For example, it has been reported that the gene products of the Ped type, which are members of the MHC I family, are of significant importance to embryonic development. More specifically, it has been reported in the case of mouse preimplantation embryos that the Q7 and Q9 genes are responsible for the “fast growth” phenotype. Therefore, it is anticipated that introduction of DNAs that provide for the expression of these and related genes, or their human or other mammalian counterparts into donor cells, will give rise to nuclear transfer embryos that grow more quickly. This is particularly desirable in the context of cross-species nuclear transfer embryos which may develop less efficiently in tissue culture than nuclear transfer embryos produced by fusion of cells or nuclei of the same species.
[0162] In particular, a DNA construct containing the Q7 and/or Q9 gene will be introduced into donor somatic cells prior to nuclear transfer. For example, an expression construct can be constructed containing a strong constitutive mammalian promoter operably linked to the Q7 and/or Q9 genes, an IRES, one or more suitable selectable markers, e.g., neomycin. ADA, DHFR, and a poly-A sequence, e.g., bGH polyA sequence. Also, it may be advantageous to further enhance Q7 and Q9 gene expression by the inclusion of insulates. It is anticipated that these genes will be expressed early on in blastocyst development as these genes are highly conserved in different species, e.g., bovines, goats, porcine, dogs cats and humans. Also, it is anticipated that donor cells can be engineered to affect other genes that enhance embryonic development. Thus, these genetically modified donor cells should produce blastocysts and preimplantation stage embryos more efficiently.
[0163] Still another aspect of the invention involves the construction of donor cells that are resistant to apoptosis. i.e., programmed cell death. It has been reported in the literature that cell death related genes are present in preimplantation stage embryos (Adams et al., Science, 281(5381): 1322-6 (1995)). Genes reported to induce apoptosis include e.g. Bad. Bok, BH3, Bik, Hrk, BNIP3 Bim L , Bad, Bid, and EGL-1. By contrast, genes that reportedly protect cells from programmed cell death include, by way of example, BcL-XL, Bcl-w, Mcl-1, A1, Nr-13, BHRF-1, LMW5-HL, ORF16, Ks-Bel-2, E1B-19K, and CED-9.
[0164] Thus, donor cells can be constructed wherein genes that induce apoptosis are “knocked out” or wherein the expression of genes that protect the cells from apoptosis is enhanced or turned on during embryonic development.
[0165] For example, this can be effected by introducing a DNA construct that provides for regulated expression of such protective genes, e.g., Bcl-2 or related genes during embryonic development. Thereby, the gene can be “turned on” by culturing the embryo under specific growth conditions. Alternatively, it can be linked to a constitutive promoter.
[0166] More specifically., a DNA construct containing a Bcl-2 gene operably linked to a regulatable or constitutive promoter, e.g. PGK, S140 CMV, ubiquitin, or β-actin, an IRES, a suitable selectable marker, and a poly-A sequence can be constructed and introduced into a desired donor mammalian cell. e.g., human keratinocyte or fibroblast.
[0167] These donor cells, when used to produce nuclear transfer embryos, should be resistant to apoptosis and thereby differentiate more efficiently in tissue culture. Thereby, the speed and/or number of suitable preimplantation embryos produced by nuclear transfer can be increased.
[0168] Another means of accomplishing the same result is to impair the expression of one or more genes that induce apoptosis. This will be effected by knock-out or by the use of antisense or ribozymes against genes that are expressed in and which induce apoptosis early on in embryonic development. Examples thereof are identified above. Cell death genes that may be expressed in the antisense orientation include BAX. Apaf-1, and capsases. Additionally, a transgene may be introduced that encodes for methylase or demethylase in the sense or antisense orientation. DNAs that encode methylase and demethylase enzymes are well known in the art. Still alternatively, donor cells may be constructed containing both modifications, i.e., impairment of apoptosis-inducing genes and enhanced expression of genes that impede or prevent apoptosis. The construction and selection of genes that affect apoptosis, and cell lines that express such genes, is disclosed in U.S. Pat. No. 5,646,008, which patent is incorporated by reference herein. Many DNAs that promote or inhibit apoptosis have been reported and are the subject of numerous patents.
[0169] Another means of enhancing cloning efficiency is to select cells of a particular cell cycle stage as the donor cell. It has been reported that this can have significant effects on nuclear transfer efficiency (Barnes et al., Mol. Reprod. Devel., 36(1): 33-41 (1993)). Different methods for selecting cells of a particular cell cycle stage have been reported and include serum starvation (Campbell et al., Nature 380: 64-66 (1996); Wilmut et al., Nature, 385: 810-3 (1997)), and chemical synchronization (Urbani et al., Exp. Cell Res., 219: 159-68 (1995)). For example, a particular cyclin DNA may be operably linked to a regulatory sequence, together with a delectable marker, e.g., green fluorescent protein (GFP), followed by the cyclin destruction box, and optionally insulation sequences to enhance cyclin and marker protein expression. Thereby, cells of a desired cell cycle can be easily visually detected and selected for use as a nuclear transfer donor. An example thereof is the cyclin D1 gene in order to select for cells that are in G1. However, any cyclin gene should be suitable for use in the claimed invention. (See, e.g., King et al., Mol. Biol. Cell. 7(9): 1343-57 (1996)).
[0170] However, a less invasive or more efficient method for producing cells of a desired cell cycle stale are needed. It is anticipated that this can be effected by genetically modifying donor cells such that they express specific cyclins under delectable conditions. Thereby, cells of a specific cell cycle can be readily discerned from other cell cycles.
[0171] Cyclins are proteins that are expressed only during specific stages of the cell cycle. They include cyclin D1, D2 and D3 in G1 phase, cyclin B1 and B2 in G2/M phase and cyclin E, A and H in S phase. These proteins are easily translated and destroyed in the cytogolcytosol. This “transient” expression of such proteins is attributable in part to the presence of a “destruction box”, which is a short amino acid sequence that is part of the protein that functions as a tag to direct the prompt destruction of these proteins via the ubiquitin pathway (Adams et al., Science. 281 (5321): 1322-26 (1998)).
[0172] In the present invention, donor cells will be constructed that express one or more of such cyclin genes under easily detectable conditions, preferably visualization. e.g. by the use of a fluorescent label. For example, a particular cyclin DNA may be operably linked to a regulatory sequence, together with a detectable marker. e.g. green fluorescent protein (GFP), followed by the cyclin destruction box, and optionally insulation sequences to enhance cyclin and/or marker protein expression. Thereby, cells of a desired cell cycle can be easily visually detected and selected for use as a nuclear transfer donor. An example thereof is the cyclin D1 gene which can be used to select for cells that are in G1. However, any cyclin gene should be suitable for use in the claimed invention. (See, e.g. King et al. Mol. Biol. Cell, 7(9):1343-57 (1996)).
[0173] As discussed, the present invention provides different methods for enhancing nuclear transfer efficiency, preferably a cross-species nuclear transfer process. While the present inventors have demonstrated that nuclei or cells of one species when inserted or fused with an enucleated oocyte of a different species can give rise to nuclear transfer embryos that produce blastocysts, which embryos can give rise to ES cell lines, the efficiency of such process is quite low. Therefore, many fusions typically need to be effected to produce a blastocyst the cells of which may be cultured to produce ES cells and ES cell lines. Yet another means for enhancing the development of nuclear transfer embryos in vitro is by optimizing culture conditions. One means of achieving this result will be to culture NT embryos under conditions impede apoptosis. With respect to this embodiment of the invention, it has been found that proteases such as capsases can cause oocyte death by apoptosis similar to other cell types. (See. Jurisicosva et al., Mol. Reprod. Devel. 51(3): 243-53 (1998)).
[0174] It is anticipated that blastocyst development will be enhanced by including in culture media used for nuclear transfer and to maintain blastocysts or culture preimplantation stage embryos one or more capsase inhibitors. Such inhibitors include by way of example capsase-4 inhibitor I, capsase-3 inhibitor I, capsase-6 inhibitor II, capsase-9 inhibitor II, and capsase-1 inhibitor I. The amount thereof will be an amount effective to inhibit apoptosis, e.g., 0.00001 to 5.0% by weight of medium, more preferably 0.01% to 1.0% by weight of medium. Thus, the foregoing methods may be used to increase the efficiency of nuclear transfer by enhancing subsequent blastocyst and embryo development in tissue culture.
[0175] After NT units of the desired size are obtained, the cells are mechanically removed from the zone and are then used to produce EG. ES or ES-like cells or cell lines. This is preferably effected by taking the clump of cells which comprise the NT unit, which typically will contain at least about 50 cells, washing such cells, and plating the cells onto a feeder layer. e.g., irradiated fibroblast cells. Typically, the cells used to obtain the stem-like cells or cell colonies will be obtained from the inner most portion of the cultured NT unit which is preferably at least 50 cells in size. However. NT units of smaller or greater cell numbers as well as cells from other portions of the NT unit may also be used to obtain ES-like cells and cell colonies.
[0176] It is further envisioned that a longer exposure of donor cell DNA to the oocyte's cytosol may facilitate the dedifferentiation process. This can be accomplished by re-cloning, i.e., by taking blastomeres from a reconstructed embryo and fusing them with a new enucleated oocyte. Alternatively, the donor cell may he fused with an enucleated oocyte and four to six hours later, without activation, chromosomes removed and fused with a younger oocyte. Activation would occur thereafter.
[0177] The cells are maintained in the feeder layer in a suitable growth medium, e.g. alpha MEM supplemented with 10% FCS and 0.1 mM β-mercaptoethanol (Sigma) and L-glutamine. The growth medium is changed as often as necessary to optimize growth. e.g., about every 2-3 days.
[0178] This culturing process results in the formation of embryonic or stem-like cells or cell lines. In the case of human cell/bovine oocyte declined NT embryos, colonies are observed by about the second day of culturing in the alpha MEM medium. However, this time may vary dependent upon the particular nuclear donor cell, specific oocyte and culturing to conditions. One skilled in the an can vary the culturing conditions as desired to optimize growth of the particular embryonic or stem-like cells. Other suitable media are disclosed herein.
[0179] Alternatively, that such cells are actual human or primate embryonic stein cells will be confirmed based on their capability of giving rise to all of mesoderm, ectoderm and endoderm tissues. This will be demonstrated by culturing ES cells produced according to the invention under appropriate conditions, e.g., as disclosed by Thomsen, U.S. Pat. No. 5,843,780, incorporated by reference in its entirety herein. Alternatively, the fact that the cells produced according to the invention are pluripotent will be confirmed by injecting such cells into an animal, e.g., a SCID mouse, or large agricultural animal, and thereafter obtaining tissues that result from said implanted cells. These implanted ES cells should give rise to all different types of differentiated tissues, i.e., mesoderm, ectoderm, and endodermal tissues.
[0180] The resultant ES. EG. ES-like cells and cell lines have numerous therapeutic and diagnostic applications. For example, such embryonic or stem-like cells may be used for cell transplantation therapies. Human embryonic or stem-like cells have application in the treatment of numerous disease conditions.
[0181] Still another object of the present invention is to improve the efficacy of nuclear transfer, e.g., cross-species nuclear transfer by introducing mitochondrial DNA of the same species as the donor cell or nucleus into the recipient oocyte before or after nuclear transfer, before or after activation, and before or after fusion and cleavage. Preferably, if the donor cell is human, human mitochondrial DNA will be derived from cells of the particular donor. e.g., liver cells and tissue.
[0182] Methods for isolating mitochondria are well known in the art. Mitochondria can be isolated from cells in tissue culture, or from tissue. The particular cells or tissue will depend upon the particular species of the donor cell. Examples of cells or tissues that may be used as sources of mitochondria include fibroblasts, epithelium, liver, lung, keratinocyte, stomach, heart, bladder, pancreas, esophageal lymphocytes, monocytes, mononuclear cells, cumulus cells, uterine cells, placental cells, intestinal cells, hematopoietic cells, and tissues containing such cells.
[0183] For example, mitochondria can be isolated from tissue culture cells and rat liver. It is anticipated that the same or similar procedures may be used to isolate mitochondria from other cells and tissues. As noted above, preferred source of mitochondria comprises human liver tissue because such cells contain a large number of mitochondria. Those skilled in the art will be able to modify the procedure as necessary, dependent upon the particular cell line or tissue. The isolated DNA can also be further purified, if desired, known methods, e.g., density gradient centrifugation.
[0184] In this regard, it is known that mouse embryonic stem (ES) cells are capable of differentiating into almost any cell type e.g., hematopoietic stem cells. Therefore, human ES or ES-like cells as well as that of other species produced according to the invention should possess similar differentiation capacity. The ES. EG and EG-like cells according to the invention will be induced to differentiate to obtain the desired cell types according to known methods. For example, the subject ES. EG and EG-like cells may be induced to differentiate into hematopoietic stem cells, muscle cells, cardiac muscle cells, liver cells, cartilage cells, epithelia) cells, urinary tract cells, etc. by culturing such cells in differentiation medium and under conditions which provide for cell differentiation. Medium and methods which result in the differentiation of embryonic stem cells are known in the art as are suitable culturing conditions.
[0185] For example, Palacios et al., Proc. Natl. Acad. Sci. USA, 92: 7530-37 (1995) teaches the production of hematopoietic stem cells from an embryonic cell line by subjecting stem cells to an induction procedure comprising initially culturing aggregates of such cells in a suspension culture medium lacking retinoic acid followed by culturing in the same medium containing retinoic acid, followed by transferral of cell aggregates to a substrate which provides for cell attachment.
[0186] Moreover, Pedersen, J. Reprod. Fertil. Dev., 6: 543-52 (1994) is a review article which references numerous articles disclosing methods for in vitro differentiation of embryonic stem cells to produce various differentiated cell types including hematopoietic cells, muscle, cardiac muscle, nerve cells, among others.
[0187] Further, Bain et al., Dev. Biol., 168:342-357 (1995) leaches in vitro differentiation of embryonic stem cells to produce neural cells which possess neuronal properties. These references are exemplar of reported methods for obtaining differentiated cells from embryonic or stem-like cells. These references and in particular the disclosures therein relating to methods for differentiating embryonic stem cells are incorporated by reference in their entirety herein.
[0188] Thus, using known methods and culture medium, one skilled in the an may culture the subject embryonic or stem-like cells to obtain desired differentiated cell types, e.g. neural cells, muscle cells, hematopoietic cells, etc. In addition, the use of inducible Bcl-2 or Bcl-x1 might be useful for enhancing in vitro development of specific cell lineages. In vivo, Bcl-2 prevents many, but not all, forms of apoptotic cell death that occur during lymphoid and neural development. A thorough discussion of how Bcl-2 expression might be used to inhibit apoptosis of relevant cell lineages following transfection of donor cells is disclosed in U.S. Pat. No. 5,646,008, which is herein incorporated by reference.
[0189] The subject embryonic or stem-like cells may be used to obtain any desired differentiated cell type. Therapeutic usages of such differentiated human cells are unparalleled. For example, human hematopoietic stem cells may be used in medical treatments requiring bone marrow transplantation. Such procedures are used to treat many diseases, e.g., late stage cancers such as ovarian cancer and leukemia, as well as diseases that compromise the immune system, such as AIDS. Hematopoietic stem cells can be obtained, e.g., by fusing adult somatic cells of a cancer or AIDS patient. e.g., epithelial cells or lymphocytes with an enucleated oocyte, e.g., bovine oocyte, obtaining embryonic or stem-like cells as described above, and culturing such cells under conditions which favor differentiation, until hematopoietic stem cells are obtained. Such hematopoietic cells may be used in the treatment of diseases including cancer and AIDS.
[0190] Alternatively, adult somatic cells from a patient with a neurological disorder may be fused with an enucleated animal oocyte, e.g., a primate or bovine oocyte, human embryonic or stem-like cells obtained therefrom, and such cells cultured under differentiation conditions to produce neural cell lines. Specific diseases treatable by transplantation of such human neural cells include, by way of example, Parkinson's disease. Alzheimer's disease, ALS and cerebral palsy, among others. In the specific case of Parkinson's disease, it has been demonstrated that transplanted fetal brain neural cells make the proper connections with surrounding cells and produce dopamine. This can result in long-term reversal of Parkinson's disease symptoms.
[0191] To allow for specific selection of differentiated cells, donor cells may be transfected with selectable markers expressed via inducible promoters, thereby permitting selection or enrichment of particular cell lineages when differentiation is induced. For example, CD34-neo may be used for selection of hematopoietic cells, Pwl-neo for muscle cells, Mash-1-neo for sympathetic neurons, Mal-neo for human CNS neurons of the grey matter of the cerebral cortex. etc.
[0192] The great advantage of the subject invention is that it provides an essentially limitless supply of isogenic or synegenic human cells suitable for transplantation. Therefore, it will obviate the significant problem associated with current transplantation methods, i.e., rejection of the transplanted tissue which may occur because of host versus graft or graft versus host rejection. Conventionally, rejection is prevented or reduced by the administration of anti-rejection drugs such as cyclosporin. However, such drugs have significant adverse side-effects. e.g., immunosuppression, carcinogenic properties, as well as being very expensive. The present invention should eliminate, or at least greatly reduce, the need for anti-rejection drugs, such as cyclosporine, imulan, FK-506, glucocorticoids, and rapamycin, and derivatives thereof.
[0193] Other diseases and conditions treatable by isogenic cell therapy include, by way of example, spinal cord injuries, multiple sclerosis, muscular dystrophy, diabetes, liver diseases, i.e., hypercholesterolemia, heart diseases, cartilage replacement, burns, foot ulcers, gastrointestinal diseases, vascular diseases, kidney disease, urinary tract disease, and aging related diseases and conditions.
[0194] Also, human embryonic or stem-like cells produced according to the invention may be used to produce genetically engineered or transgenic human differentiated cells. Essentially, this will be effected by introducing a desired gene or genes, which may be heterologous or removing all or pail of an endogenous gene or genes of human embryonic or stem-like cells produced according to the invention, and allowing such cells to differentiate into the desired cell type. A preferred method for achieving such modification is by homologous recombination because such technique can be used to insert, delete or modify a gene or genes at a specific site or sites in the stem-like cell genome.
[0195] This methodology can be used to replace defective genes. e.g. defective immune system genes, cystic fibrosis genes, or to introduce genes which result in the expression of therapeutically beneficial proteins such as growth factors, lymphokines, cytokines, enzymes etc. For example, the gene encoding brain derived growth factor may be introduced into human embryonic or stem-like cells, the cells differentiated into neural cells and the cells transplanted into a Parkinson's patient to retard the loss of neural cells during such disease.
[0196] Previously, cell types transfected with BDNF varied from primary cells to immortalized cell lines, either neural or non-neural (myoblast and fibroblast) derived cells. For example, astrocytes have been transfected with BDNF gene using retroviral vectors, and the cells grafted into a rat model of Parkinson's disease (Yoshimoto et al., Brain Research, 691:25-36, (1995)).
[0197] This ex vivo therapy reduced Parkinson's-like symptoms in the rats up to 45% 32 days after transfer. Also, the tyrosine hydroxylase gene has been placed into astrocytes with similar results (Lundberg et al., Develop. Neurol., 139:39-53 (1996) and references cited therein).
[0198] However, such ex vivo systems have problems. In particular, retroviral vectors currently used are down-regulated in vivo and the transgene is only transiently expressed (review by Mulligan, Science, 260: 926-932 (1993)). Also, such studies used primary cells, astrocytes, which have finite life span and replicate slowly. Such properties adversely affect the rate of transfection and impede selection of stably transfected cells. Moreover, it is almost impossible to propagate a large population of gene targeted primary cells to be used in homologous recombination techniques.
[0199] By contrast, the difficulties associated with retroviral systems should be eliminated by the use of human ES and ES-like cells and cell lines. It has been demonstrated previously by the subject assignee that cattle and pig embryonic cell lines can be transfected and selected for stable integration of heterologous DNA. Such methods are described in commonly assigned U.S. Ser. No. 08/626,054, filed Apr. 1, 1996, now U.S. Pat. No. 5,905,042, incorporated by reference in its entirety. Therefore, using such methods or other known methods, desired genes may be introduced into the subject ES and ES-like cells, and the cells differentiated into desired cell types, e.g., hematopoietic cells, neural cells, pancreatic cells, cartilage cells. etc.
[0200] Genes which maybe introduced into the subject EG, ES. ES-like cells include, by way of example, epidermal growth factor, basic fibroblast growth factor, glial derived neurotrophic growth factor, insulin-like growth factor (I and II), neurotrophin-3, neurotrophin-4/5, ciliary neurotrophic factor, AFT-1, cytokine genes (interleukins, interferons, colony stimulating factors, tumor necrosis factors (alpha and beta), etc.), genes encoding therapeutic enzymes, collagen, human serum albumin, etc.
[0201] In addition, it is also possible to use one of the negative selection systems now known in the art for eliminating therapeutic cells from a patient if necessary. For example, donor cells transfected with the thymidine kinase (TK) gene will lead to the production of embryonic cells containing the TK gene. Differentiation of these cells will lead to the isolation of therapeutic cells of interest which also express the TK gene. Such cells may be selectively eliminated at any time from a patient upon gancyclovir administration. Such a negative selection system is described in U.S. Pat. No. 5,698,446, and is herein incorporated by reference.
[0202] The subject ES, ES-like and EC cells may be used as an in vitro model of differentiation, in particular for the study of genes which are involved in the regulation of early development.
[0203] Also, differentiated cell tissues and organs using the subject embryonic or stem-like cells may be used in drug studies.
[0204] Further, the subject cells may be used to express recombinant DNAs.
[0205] Still further, the subject embryonic or stem-like cells may be used as nuclear donors for the production of other embryonic or stem-like cells and cell colonies.
[0206] Also, cultured inner cell mass, or stem cells, produced according to the invention may be introduced into animals. e.g., SCID mice, cows, pigs, e.g., under the renal capsule or intramuscular and used to produce a teratoma therein. This teratoma can be used to derive different tissue types. Also, the inner cell mass produced by X-species nuclear transfer may be introduced together with a biodegradable, biocompatible polymer matrix that provides for the formation of 3-dimensional tissues. After tissue formation, the polymer degrades, ideally just leaving the donor tissue, e.g., cardiac, pancreatic, neural, lung, liver. In some instances, it may be advantageous to include growth factors and proteins that promote angiogenesis. Alternatively, the formation of tissues can be effected totally in vitro, with appropriate culture media and conditions, growth factors, and biodegradable polymer matrices.
EXAMPLES
Example 1
[0207] We have developed a method, using nuclear transplantation, to produce transgenic embryonic stem (ES)-like cells from fetal bovine fibroblasts. These cells, when reintroduced into preimplantation embryos, differentiated into derivatives from the three embryonic germ layers, ectoderm, mesoderm, and endoderm, in 5-month-old animals. Six out of seven (86%) calves born were found to be chimeric for at least one tissue. These experiments demonstrate that somatic cells can be genetically modified and then de-differentiated by nuclear transfer into ES-like cells, opening the possibility of using them in differentiation studies and human cell therapy.
[0208] Embryonic stem (ES) cells have been available for several strains of mice for many years and have been shown to be capable of contributing to each of the tissues of the animal when combined with a host embryo to form a chimera. Techniques have been developed for inducing the differentiation of mouses ES cells in vitro and successfully transplanting them into recipient mice. Success in developing pluripotent cell lines from large animal species, such as bovine, has been minimal. Production of putative bovine ES cells vas first reported by Saito et al., and later, a similar type of stem-like cells w as reported to direct development through organogenesis. Bovine ES cells that are capable of complete differentiation to term, in vivo, have not been reported. Little success has been achieved in inducing ES cells to differentiate into a specified tissue in vitro or in the selecting specific cells, out of the many other types of cells that are present, following the induction of in vitro differention.
[0209] The objectives of this study were to develop an efficient procedure for producing bovine ES-like cells, to lest the pluripotency of these cells in vivo by forming chimeras with host embryos, and to develop an efficient method for genetic modification of the cells using somatic cell nuclear transplantation.
[0210] Results. Production of transgenic embryo-derived pluripotent ES-like cell colonies. As one approach to producing transgenic cattle, putative bovine ES-like cells were derived from embryos. In vitro maturation and fertilization of oocytes and in vitro culture of the embryos to the blastocyst stage produced 49 embryos at day 7. Blastocysts were mechanically dissected and plated on mitotically inactivated fetal mouse fibroblast feeder layers. Twenty-seven inner cell masses attached to the feeder layer grew as ES-like cell colonies and successfully survived passaging over at least 12 months without differentiation. These colonies had well-defined edges. Cells in these colonies had a high nuclear to cytoplasmic ratio and a high density of cytoplasmic lipid granules, and were negative for cytokeratin and vimentin. Unlike mouse ES cells, bovine ES cells eventually formed single layer sheets (FIG. 1A) and were alkaline phosphatase negative.
[0211] The method of producing transgenic bovine ES-like cells also differed from procedures used for the mouse (FIG. 2A). Bovine ES-like cells, unlike mouse ES cells, do not survive replating when trypsinization is performed; therefore, mechanical passage was used instead. Passage of the cells mechanically involves removing a group of cells, containing a minimum of 50 to 100 cells, and transferring these to fresh feeder layers. Because single cell suspensions could not be passaged, it was not possible to use electroporation for DNA transfection or to clonally propagate transgenic cells. Therefore microinjection of DNA into the nucleus of individual cells was used as an alternative method. Approximately 500 to 1000 cells could be injected per hour, and injection volume vas based on nuclear swelling. Three different cell lines ere used. A cytomegalovirus (CMV)-β-galactosidase-neomycin (β-Geo) cassette as delivered into the nucleus of ES-like cells. Five, three, and zero stable. G418 selected transgenic colonies were produced out of 3753, 3508S and 3502 injected cells, respectively. We did not determine if these colonies were derived from single or multiple transgenic cells. During G418 selection the original colony essentially disappeared before growth of the transgenic cells began, indicating a possible clonal origin; however, the possibility of having produced a transgenic colony from two or more closely placed transgenic cells cannot be ruled out. β-galactosidase expression as consistently high in all colonies, although not all cells within a colony expressed the gene (FIG. 1B). PCR amplification of a segment of the transgene also confirmed that the cells were transgenic (FIG. 1E).
[0212] Production of transgenic somatic cell-derived bovine pluripotent ES-like cell colonies. Although transgenic ES-like cells can be produced by microinjection, the generation of a large number of transgenic ES-like cells and clonal propagation was not achieved. Therefore, we took another approach (FIG. 2B) that involved transfection of bovine fetal fibroblasts and fusion of the transgenic fibroblast cells to enucleated oocytes to produce blastocyst stage nuclear transplant embryos. These embryos were then plated on fibroblast feeder layers to produce transgenic ES-like cell colonies. Bovine fibroblasts were obtained from 55 day fetus, and grown and transfected by electroporation using standard methods (FIG. 1C). Three hundred and thirty enucleated mature bovine oocytes were reconstructed with actively dividing fibroblasts. Thirty-seven (11%) blastocytes (day 7.5) were obtained and ES-like cell lines were established from 22 (59%) of these. Out of 22 cell lines, 21 were positive for the transgene after PCR amplification of the β-galactosidase fragment. The negative ES-like colony could have originated from a neomycin-resistant fibroblast that lost the β-galactosidase gene. Fibroblast-derived ES-like cell colonies showed morphology and cytoplasmic marker characteristics identical to those of embryo-derived ES-like cells (FIG. 1D). Furthermore, colonies were passaged for several months without differentiation, even, in one case, when a colony as derived from a senescent, nondividing fibroblast cell line.
[0213] Production of chimeric calves. In order to determine the potency of bovine embryo- (passage 10) and fibroblast-derived ES-like cells (passage 3) in vivo. 8 to 10 cells were introduced into day 3 in vitro produced embryos, cultured in vitro until day 7.5 and transferred into synchronized recipients. Five calves were born from embryos that received transgenic embryo-derived ES-like cells, and seven calves ere born from embryos that received transgenic nuclear-transfer (NT)-derived ES-like cells (Table 1). All the animals were phenotypically normal.
TABLE 1 Production of transgenic calves using embryo, and NT-derived ES like cells Injected Blastocyst Blastocyst Calves Transgenic embryos produced (%) transferred born calves* Embryo ES-like cells 70 16 (23) 16 5 3 NT ES-like cells 99 22 (22) 10 7 6
[0214] All the animals were slaughtered at 5 months of age, with the exemption of calf 904 , which was killed at 45 days of age. Genomic DNA was isolated from a spectrum of tissues (skin, muscle, brain, liver, spleen, kidney, heart, lung, mammary gland, intestine, and gonads) from each animal, amplified using β-Geo primers, and probed using standard-protocol Southern blot analysis. Results were positive in at least one tissue in nine calves and in two or more tissues in six calves. Oocytes were found to be positive in one animal (FIG. 3). The limited presence of transgenic cells in the newborn animals could be attributed to the fact that not all the ES-like cells were incorporated into the developing morulas; moreover, among those cells that did incorporate, degree of pluripotency may have varied.
[0215] Fluorescent in situ hybridization (FISH) analysis was performed in spleen tissue from calf 911 (FIG. 4A), and testis of calf 903 (FIG. 1C). Positive hybridization signals were identified in both tissues. In the spleen. 32% of nuclei ({fraction (82/256)}) exhibited green signals compared with negative spleen in which only 1% of nuclei ({fraction (2/231)}) were classified as carrying green signals. Testis specimens were not presented as a single monolayer of cells: therefore, percentage of positive cells was not assessed; however, positive signals were detected inside the seminiferous tubules.
[0216] Discussion. The first objective of this study was to produce bovine pluripotent ES-like cells. ES-like cells are derived from an early stage embryo of the inner cell mass (ICM) directly, and, therefore, should retain the morphology and cellular characteristics of the ICM. In the mouse. ES cells grow as colonies with a defined margin, and cells have high nuclear to cytoplasmic ratio and high density of lipid inclusions similar to the ICM. Our bovine cells derived both from embryos and NT fibroblasts, also retained these characteristics. The expression of various cytoplasmic markers has also been used to indicate an ICM-like quality of mouse ES cells. In the bovine, ES-like cells derived either from embryonic or somatic cell sources, do not express differentiation markers such as vimentin and cytokeratin in a pattern similar to the ICM; however, these cells are alkaline phosphatase negative. The second characteristic of a pluripotent embryonic cell is that it can be grown over many passages without showing signs of differentiation. In this study, and other preliminary work (1), bovine ICM-derived cells were passaged for over 1 year without losing the morphological and cellular similarities to the ICM. The third and most important characteristic used to define ES-like cells is that, upon introduction into a preimplantation) embryo, they are able to colonize the ectodermal, mesodermal, and endodermal tissues and the germ line, as the host embryo develops and differentiates. In this study it was shown that both embryonic and fibroblast-derived ES-like bovine ells are capable of giving rise to multiple tissues in 5-month-old animals. Our results demonstrate that cells derived from somatic and embryonic sources possess functional and phenotypic characteristics of pluripotent ES-like cells.
[0217] Much work has been done in many different species toward developing methods of producing ES cells; how ever, little success has been reported at meeting all the criteria listed above. In rabbit (6) production of chimeric offspring was reported, but no chimerism in gonads was demonstrated. In hamster (7, 8) and cow (3, 4), cells were grown in vitro however, no chimeric animals were produced. This is the first published report demonstrating transgenic chimerism in full-term live mammals, including in gonadal tissue from a species other than a mouse. However, until germline transmission is demonstrated, we refer to our cells as “pluripotent or ES-like cells” instead of ES cells.
[0218] The results in this study indicate that, although genetic modifications could be made in bovine ES-like cells by microinjection, and transgenic cells could be selected by a standard neomycin resistance approach, limitations in the number of cells that can be microinjected, the slow growth of the cells, and our inability to clonally propagate the ES-like cells limits the usefulness of this approach, particularly for gene targeting. This is one important difference between bovine ES-like cells and mouse ES cells. Aside from the fact that care must be taken to prevent differentiation, mouse ES cells can be readily grown in culture, clonally propagated, transfected by standard high-volume gene transfer methods, and in many cases, exhibit high-efficiency homologous recombination. In our system, the low transfection efficiency of bovine ES-like cells prevents the possibility of using direct ES-like cell transfection for gene targeting.
[0219] An alternative method of making genetic modifications in bovine ES-like cells is to genetically modify fibroblast cells and then produce embryos by nuclear transplantation. Genetic modification is relatively simple with fibroblast cells, which are easy to grow, transfect and clonally propagate. Furthermore, gene targeting and selection for homozygous lines in vitro have been successful in human fibroblast lines.
[0220] This study demonstrates that ES-like cells can be produced from bovine embryos, which can be cultured without a change in morphology for indefinite periods in vitro and retain the ability to give rise to tissues derived from all three gene layers in offspring. Furthermore, using nuclear transplantation., these cells can be produced from genetically modified fibroblasts. This system could be useful for the in vitro production of genetically modified bovine cells to be used for cell transplant therapies for many different human diseases.
[0221] Experimental Protocol
[0222] In vitro maturation of bovine oocytes. Ovaries were recovered at a slaughterhouse, placed in warm phosphate-buffered saline (PBS) (34° C.) and brought to the laboratory within a limit of 8 h. Each follicle of more than 2 mm in diameter was aseptically aspirated with an 18 gauge needle. Search of oocytes was performed in modified Tyrode's medium (TL Hepes). Oocytes with a homogeneous cytoplasm, considerable perivitelline space and intact cumulus cells were placed in maturation medium M199 (GIBCO, Grand Island, N.Y.), a 10% fetal calf serum (FCS), 5 μl/ml bovine follicle-stimulating hormone (Nobl, Sioux Center, Iowa), 5 μl/ml bovine luteinizing hormone (Nobl), and 10 μl/ml Pen-strep (Sigma, St. Louis, Mo.) for 22 h at 38.5° C. and 5% CO 2 .
[0223] In vitro fertilization of bovine oocytes. Twenty-two hours post-maturation, oocytes were placed in fertilization medium (5 ml CR2-Specialty medium, stock solution 100 U/ml penicillin, 100 μg/ml streptomycin, 0.005 μg/ml phenol red, 30 mg bovine serum albumin fatty acid free, 5 μg/ml sodium heparin). A unit of frozen semen was thawed and placed on top of a Percoll layer that contains 90% Percoll (Sigma) and one part 10 modified sperm TL plus, 45% Percoll (one part of 90% Percoll stock solution and one part sperm TI, without BSA). Dead sperm were separated from live sperm by centrifugation at 700 G for 30 min. Sperm pellet was resuspended at a final concentration of 500,000 sperm/ml. After 12 h in culture at 38.5° C. and 5% CO 2 , eggs were removed and placed in CR2 medium with 3 mg/ml BSA.
[0224] Embryo culture. During the first 3 days after fertilization, embryos were cultured in 500 μl well plates with mouse embryonic fibroblast (MF) feeder layers and CR2 with 6 mg/ml BSA. On day 4, embryos were transferred to 500 μl well plates with MF feeder layers, CR2 with 6 mg/ml BSA, and 10% FCS until blastocyst stage day 7 post-insemination).
[0225] ES-like cell culture. Blastocysts were placed in a 32 mm plate (Nunc, Rochester, N.Y.) with mitotically inactivated MF feeder layer and ES medium (Alpha MEM, 10% fetal calf serum, 4 111 /ml antibiotic-antimycotic, 2.8 μl/ml 2-mercaptoethanol, 0.3 mg/ml L-glutamine, and 1 μl/ml tylosin tartrate) equilibrated a day in advance at 38.5° C. and 5% CO 2 . Using a 22 gauge needle, blastocysts' zona pellucida and trophoblast were mechanically removed. The remaining ICM was placed underneath the MF. After 1 week in culture, ES-like cells were passaged to a fresh mitotically inactivated MF. Inactivation of MF was performed by exposing them to gamma radiation (2956 rads). ES-like cells were passaged by cutting a small piece (50 to 100 cells) of the colony and placed on top MF feeder layers using a pulled Pasteur pipette.
[0226] Nuclear transplantation. Eighteen hours post-maturation, oocytes were placed in a 100 μl drop of TL HECM-Hepes under mineral oil (Sigma). Oocyte enucleation (extraction of chromosomes) was performed using a beveled glass pipette of 25 μm diameter. Evaluation of enucleation was done by exposure of individual oocytes previously cultured for 15 min in 1 μg/ml of bisBENZIMIDE (Hoechst 33342; Sigma) in TL HECM-Hepes under ultraviolet light. Donor cells were placed in the perivitelline space and fused with the egg's cytoplasm at 23 h post-maturation. Oocytes and donor cell were placed into 4 ml medium made of 50% SOR2 fusion medium (0.25 M D-sorbitol (Sigma), 100 (M CaOAc (Sigma), 0.5 mM magnesium acetate (Sigma), 1.0 g BSA (Sigma), and 50% HECM-Hepes for 2 min. Eggs were then placed between the electrodes of a 500 μm fusion chamber. Once the eggs were aligned, a pulse of 90 V was administered over 15 μs. Eggs were then returned to the 50/50 medium of SOR2 and HECM/Hepes for 2 min and, finally, placed into a 500 μl drop of CR2 at 38.5° C. and 5% CO 2 until activation.
[0227] Oocyte activation. Activation was performed in general as described by Forrester et al., Proc. Natl, acad. Sci. USA 88: 7514-77 (1991) and Palaclos et al., Dev. Biol., 92: 7530-4 (1995). Briefly, 25 to 27 h post-maturation oocytes were incubated in 5 μm ionomycin (Cal Biochem, La Jolla, Calif.), and 2 mM of 6-dimethylaminopurine (DMAP; Sigma) in CR2 with 3 mg/ml of BSA (fatty acid free; Sigma). After activation, eggs were washed in HECM/Hepes five times and placed for culture in a 500 μl well of MF and CR2 with 3 mg/ml of BSA (fatty acid free) at 38.5° C. and 5% CO 2 .
[0228] Transgenic ES-like cell production. Five micrograms per milliliter of a β-Geo cassette gene were microinjected into the nuclei of bovine ES-like cells. Twenty four to forth-eight hours after microinjection, 150 μg/ml of G418 was added to the culture medium. After 3 weeks under selection, a colony was considered transgenic upon DNA screening by PCR and ethidium bromide gel, and by β-galactosidase staining.
[0229] Bovine fibroblast production and electroporation. Bovine fibroblasts were produced from a 55-day-old fetus as follows. Under sterile conditions, the livers, intestines, and beads of the fetuses were discarded. The remaining parts of the fetuses were carefully minced and placed in a solution of Dulbecco's phosphate buffered saline (dpbs) with 0.08% trypsin (Difco, Detroit, Mich.) and 0.02% EDTA (Sigma). After 30 min incubation at 37° C. the supernatant was discarded and the pellet resuspended with trypsin-EDTA/dPBS. After 30 min incubation, the supernatant was removed and centrifuged at 300 G for 10 min. The pellet of cells was then resuspended with ES culture medium and plated in polystyrene tissue culture dishes (25010; Corning, Charlotte, N.C.). After two passages, cells were electroporated with a β-Geo cassette gene with the protocol described by Invitrogen (San Diego, Calif.) for COS cells (11). After 3 weeks under 400 μg per ml of G418 selection, fibroblasts were considered transgenic upon DNA screening by PCR and ethidium bromide gel, and by β-galactosidase staining.
[0230] Alkaline phosphatase staining. Culture medium was removed from the plates and cells were fixed with 4% paraformaldehyde for 20 min. Cells were washed three times in Tris-maleate buffer (3.6 g Trizma base [Sigma], in 1 L water, pH raised to 9.0 with 1 M maleic acid) for 10 min each wash. The last wash was removed and the staining solution (Tris-maleate buffer, 200 μl of a 0.5 mM MgCl 2 , naphthol A5-MX phosphate [Sigma]), 0.4 mg/ml, Fast blue [Sigma], 1 mg/ml) was added to the cells for 15 to 20 min. Once blue cells were detected, the reaction was stopped by adding PBS which brought the pH to 7.4
[0231] Chimera production. Seventy-two hours after in vitro fertilization (eight cell stage), embryos were placed in manipulation medium (HECM/Hepes with 10% FCS and 7.5 μg/ml of cytochalasin B [Sigma]). ES-like cells were dissociated using 0.08% trypsin (Difco) and 0.02% EDTA in PBS during 25 to 30 min. Using a 15-20 μl/ml diameter beveled pipette, 8 to 10 cells were introduced into the embryos. Embryos were placed in a 500 μl culture drop (MF feeder layer, CR2 with 6 mg/ml of BSA and 10% FCS).
[0232] Immunohistochemical studies. Primary antibodies specific against cytokeratin 8-18 (Sigma) and vimentin (Sigma) were used in ES-like cell cultures. Cells were plated on sterile glass slides, fixed in 2% paraformaldehyde, and extracted with cold (−20° C.) acetone. Cells were incubated with primary antibody dilutions in PBS containing 0.5% BSA (PBSA) for 1 h at room temperature. Slides were then rinsed three times in PBSA with changes of rinse solution every 10 min, and incubated for 1 h in fluorescein 5-isothiocyanate (FITC) conjugated anti-mouse IgG (Sigma). After rinsing in PBSA for 30 min, cover slips were mounted in 50% glycerol and observed under a fluorescence microscope (8).
[0233] β-galactosidase staining. Culture medium was removed from the plates, and cells were fixed with 2% glutaraldehyde in PBS. Then cells were washed three times with PBS and color substrate (5 mM K 3 Fe(CN) 6 , 5 mM K 4 Fe(CN) 6 , 1 mM MgCl 2 , 1 mg/ml X-gal in PBS, pH 7.0-7.5) was added for 3 h (12).
[0234] PCR analysis and blot analysis. Analysis of transfected cells and tissue from 5-month-old animals was performed using a sense primer (ACT3βGeo, a 21 base CGCTGTGGTACACGCTGTGCG) and antisense primer (ACT4βGEO, 1 22 base CACCATCCAGTGCAGGAGCTCG [Amilof Biotech, Boston, Mass.). Reactions were run for 35 cycles (1) heated at 95° C. for 30 s (2) primers were annealed at 65° C. for 1 min, (3) extended for 2 min at 72° C., followed by 10 min extension at 72° C. The amplified product was a 782 bp fragment. Sample analysis was performed by separating by size in a (1%) TAE agarose gel electrophoresis containing ethidium bromide. Products were sized by comparison with markers consisting of 1444 bp, 943 bp, 754 bp, 585 bp, 458 bp, 341 bp, 258 bp, 153 bp, and 105 bp. DNA was then handled according to standard Southern blot analysis protocols. Briefly, DNA was transferred to Zetabind (Cuno, Meriden, Conn.) by capillary transfer and probed with a gel-purified 289 bp ClaI to EcoRV fragment labeled with “PdCTP using random primed labeling kit (Boehringer Mannheim, Indianapolis, Ind.). Hybridization was done at 42° C. overnight. After washing, the blot was exposed to Biomax film (Kodak, Rochester, N.Y.) overnight. Nontransgenic fibroblasts and water were used as negative controls, and transgenic cells for β-Geo and template were used as positive control. When oocytes were analyzed, ovarian follicles were aspirated with a syringe using an 18 gauge needle. Eggs' granulose cells were removed by vortexing the oocyte/cumulus cell complex in 5 mg/ml of hyaluronidase (Sigma) in PBS. Oocytes were washed five times in PBS before DNA isolation.
[0235] FISH analysis. Samples were frozen and made onto slides either by slightly pressing the sample against the slide (for spleen slides) or by cryosections (for testis slides), βGeo DNA was linearized with ScaI and biotin-labeled by nick translation reaction. An aliquot of the biotin-labeled DNA was run on a gel and transferred to a membrane, and a streptavidin-alkaline phosphatase assay was performed to detect the size of labeled fragments and quantity of biotin incorporation. The labeled DNA was then co-precipitated with salmon sperm DNA as carrier. A number of single-target single-color FISH assays were performed using varied concentrations of labeled DNA as a probe (250-500 ng). The specimens were washed in 70% acetic acid and digested in pepsin (0.01% in 0.01 M HCl at 37° C.) before denaturation. Testis slides were incubated in pepsin at room temperature for 10 min before warming to 37° C. Denaturation was performed at 75° C. for both chromosomal and probe DNAs and hybridization was allowed to occur for approximately 60 h. Post-hybridization washes included three 5 min washes in 50% formamide/2×SSC and three 5 min washes in 2×SSC at 43° C. Immunochemical detection was achieved with consecutive incubations in FITC-avidin, biotinylated anti-avidin and FITC avidin (Vector, Burlingame, Vt.). Chromatin was counter-stained with DAPI (0.01 μg/ml on antifade; Boehringer Mannheim). After hybridization, slides were coded and blindly analyzed. Analysis was performed in an Olympus BX-60 fluorescence microscope using interference filter sets for single band (DAPI and FITC) and triple band (DAPI, FITC, Texas red). Gray images were acquired using a CCD Camera (Photometrics, Phoenix, Ariz.) and combined using the Oncor (Gaithersburg, Md.) image software.
REFERENCES
[0236] (1) Forrester et al., Proc. Natl. Acad. Sci. USA 88:7514-7577 (1991).
[0237] (2) Palaclos et al., Dev. Biol., 92:7530-7534 (1995).
[0238] (3) Saito et al., Roux's Arch. Dev. Biol., 201: 134-141 (1992).
[0239] (4) Slice et al., Biol. Reprod. 54: 100-110 (1996).
[0240] (5) Cibelli et al., Theriogonology 47: 241 (1997).
[0241] (6) Schoonjans et al., Mol. Reprod. Dev., 45: 439-443 (1996).
[0242] (7) Doelschman et al., Dev. Biol., 127: 224-227 (1988).
[0243] (8). Piedrahita et al., Theriogenology, 34: 879-901 (1990).
[0244] (9) Brown et al., Science, 277: 831-834 (1997).
[0245] (10) Susko-Parrish et al., Dev. Biol., 166: 729-739 (1994).
[0246] (11) Invitrogen, The Electroporator manual, Version 3, San Diego, Calif.
[0247] (12) Hill et al., Methods Enzymol., 225: 664-681 (1993).
[0248] Although the present invention has been described in detail with reference to examples above, it is understood that various modifications can be made without departing from the spirit of the invention, and would be readily known to the skilled artisan. All cited patents and publications referred to in this application are herein incorporated by reference in their entirety.
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DNA
Artificial Sequence
Description of Artificial Sequence Primer
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cgctgtggta cacgctgtgc g 21
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DNA
Artificial Sequence
Description of Artificial Sequence Primer
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caccatccag tgcaggagct cg 22
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This invention describes a novel method of agricultural animal production that provides animals with optimum growth characteristics in a reliable and cost-effective manner. The invention utilizes a novel combination of Nuclear Transfer (NT) and Embryonic Stem (ES) cell technologies that improves the efficiency of delivering optimized animals and facilitates the introduction of genetic modifications into farm animals.
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FIELD OF THE INVENTION
This invention relates to agricultural implements. More particularly, to implements for laying and retrieving/retracting protective netting and other crop protection materials onto/from agricultural crops, including, but not limited to berries, kiwi, apples, grapes, or any other crop which is grown in a row formation or on a trellis, to protect the plants from predators and/or other potential damage from weather i.e., frost, rain, hail, wind and sun, and to enhance growth and productivity.
BACKGROUND OF THE INVENTION
Implements for applying protective coverings on various surfaces have been previously known and used. Many devices have been used in agriculture for laying a covering on the ground or protecting certain types of agricultural plants. Typically, these devices are used in conjunction with a tractor and a normal hitch system utilizing hydraulic equipment.
The main purpose of the protective coverings of the present invention is the prevention of damage caused by particular animals, most notably birds, which feed on the various agricultural plants, most particular finches, starlings and sparrows, and by other potential damages as the result of weather i.e., frost, rain, hail, wind and sun. In the case of vineyards, the birds feed on the foliage and grapes, eventually damaging the crop. By applying a protective covering over the plants, the nuisance birds are prevented from damaging the crop and the crops are protected from damaging weather. The present invention is directed at applying and retrieving such protective coverings.
Typically, large bulk rolls of coverings have been dispensed on, or retrieved from, crops by elevating the rolls above the crops and unrolling/retrieving the covering onto the crops. Due to the great weight and unwieldy nature of the roll, this method may be quite dangerous and difficult. The present invention provides an easier and more controlled method, in that the bulk rolls are placed low to the ground for greater safety and stability and the reusable coverings may be retrieved onto small spools that are easy to manhandle, move and store and reuse.
Some machines that spread or provide covering for plants include the following:
U.S. Pat. No. 3,395,485, issued to Ricklidge on Aug. 6, 1968, discloses a crop protecting plastic dispensing mechanism attachment for a tractor or jeep which is moved between rows of fruit trees and dispenses a thin layer of plastic from a large roll through rollers and over the row of trees.
U.S. Pat. No. 1,957,994, issued to Eccher on May 8, 1934, discloses a motorized wheeled frame for dispensing covering material from a roll on the frame over trees in an orchard.
U.S. Pat. No. 4,318,514, issued to Weberg on Mar. 9, 1982, discloses a machine for applying and retracting a protective covering to agriculture plants. The implement is supportively attached by forward and rearward attachment mechanisms to a tractor and movably supported additionally by a coaster wheel laterally spaced from the tractor. Vertically oriented supports and rearward attachment mechanisms and front attachment to a wheel to support a horizontally oriented, substantially rectangular frame. A rotatable shaft mechanism attached to a universal joint is supported at the ends by shaft supports which extend upwardly from the rearward portion of the frame.
U.S. Pat. No. 3,791,069, issued to Nelson on Feb. 12, 1974, discloses an orchard tree covering device for use in placing individual covers or strips of cover material over orchard trees to prevent frost damage. The device is adapted to fit on conventional tractors and includes an adjustable elevational support and a cover holding magazine. The magazine is designed to hold a plurality of covers and includes means for selectively releasing individual covers onto trees below. In an alternate form, the covers are connected in trips and rolled onto spools. The strips may then be reeled out by the device over long rows of trees.
The present invention provides improved implements and methods of laying and retrieving protective covering materials over crops to prevent damage to said crops.
SUMMARY OF THE INVENTION
The present invention provides improved implements and methods for dispensing and retrieving protective crop covering materials (PCCM), such as, but not limited to, netting, such as bi-axially oriented polypropylene netting, films, such as blown poly films, ether cloth fabrics, plastic sheets and woven or nonwoven fabrics, on/from crops, particularly vineyard crops, to protect the plants from nuisance birds and weather conditions which cause damage to the crops. Basically, there is disclosed herein a system for layout of PCCM from a bulk roll of PCCM onto crops, a system for retrieving the PCCM from the crops and disposing it or storing said PCCM on reusable spools and a system for layout of the PCCM from the reusable spools.
The bulk roll layout system generally consists of a rolling cradle utilizing powered or idler rollers to layout bulk rolls of material from a low ground profile, wherein the roll is carried between and parallel with the rows of crops, up and over the crop through a sweep attached to a tower which reduces the material as it leaves the rolls and enters the sweep and then expands the material as it is introduced onto the crop row. This rolling cradle can be mounted on a dedicated trailer or in a frame that is designed to attach to a standard trailer.
The retrieval system consists of a hydraulically driven arbor shaft (preferably a 11/2 arbor shaft) that accepts spools for retrieval of PCCM for reuse or disposal. The shaft is mounted into a frame that is then hitched to a tractor. The PCCM is retrieved evenly onto plastic spools for reuse at a later time or onto a permanent spool that facilitates disposal in tightly compacted rolls. PCCM is pulled off the vine row utilizing the same tower and sweep arrangement used in the above mentioned bulk roll laying system. This tower arrangement is manipulated over the rows of crops by attaching it to the same frame that carries the retrieval head. Again, the material is brought from a low position in the row, elevated over the row, reduced and then expanded. In retrieving the product the opposite action takes place in that the material is lifted off the row, run through the tower sweep, reduced and put back on the spool which again is at a ground level profile.
In the system for layout of the PCCM from the reusable spools, the reusable spools of wound PCCM are taken from storage and reused by unrolling them onto the rows of crops. The system is basically the same as that of the retrieval system except that the spool of wound PCCM is mounted on the tower rather than the sweep and allowed to unroll onto the crops.
The object of the present inventions is to efficiently and effectively layout, retrieve and store PCCM, which are used to protect crops from nuisance animals, most notably vines from particular birds, and damaging weather.
A further objective is to provide a system which minimizes crop damage during the covering and uncovering process.
A further objective is to provide a crop covering system that utilizes elements, some of which were formerly thought to be single use items, which may be easily stored and reused and inexpensive machinery, which reduces manual labor and increases speed of application and retrieval of the coverings.
A further objective is to provide such a device that is adapted to be mounted to conventional farm tractors.
A further objective is to provide a system of applying crop protection materials from a low to ground profile to up and over the row so that the majority of the weight of the material is close to the ground both in laying out and retrieving material instead of being suspended above the crops.
A further objective is to provide a method of handling protective coverings that does not require the use of special material handling equipment
These and other objects and advantages will become evident upon reading the following description which, taken with accompanying drawings, describe a preferred and alternate embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is perspective view of a protective covering layout system.
FIG. 2 is a detailed view of a sweep.
FIG. 3 is a blow-up proportional view of a sweep.
FIGS. 4-5 are perspective views of a dispersing guide.
FIG. 6 is an illustrative demonstration of a laying of netting upon targeted crops.
FIG. 7 is a rear perspective view of a protective covering layout system in progress.
FIG. 8 is a top view of a protective covering layout system in progress.
FIG. 9 is a perspective view of a protective covering retrieval system.
FIG. 10 is a perspective view of a levelwind system.
FIGS. 10a and 10b are illustrative views of the arbor shaft and the bolted flange.
FIG. 11 is a perspective view of a proximal half of a permanent spool.
FIG. 12 is a perspective view of a distal half of a permanent spool.
FIG. 13 is a perspective view of the resulting wound netting after retrieval.
FIG. 14 is a perspective view of an alternative protective covering layout system utilizing a reusable distribution spool of netting.
FIG. 15 is a detailed perspective view of a mounted distribution spool.
FIG. 16 is an illustrative view of mounting clamps mounting multiple booms onto a tower.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention discloses generally a bulk PCCM (for the purpose of discussing the drawings and the embodiments below, netting will be used as an example of the PCCM, but it should be known that any PCCM may be used) roll layout system, a net retrieval system for disposal or reuse and a spooled roll layout system. The layout and retrieval systems incorporate a low profile carrier for bulk rolls or individual spools which may be stored and reused. Such a low profile carrier provides a safe method for transporting rolls or spools through fields and facilitates ease of loading and unloading.
FIGS. 1-4 disclose a tower and sweep arrangement that places netting over vine rows for protection of said rows. FIG. 1 illustrates the bulk netting roll layout system (BRLS), generally designated as 10. The BRLS carries a bulk roll of netting and dispenses the netting over crops. The BRLS consists of a trailer 12 which may be hitched to a tractor 14 (not fully shown) via a standard hitch system 16, which incorporates an optional auxiliary hydraulic system 18. The trailer 12 carries a rolling cradle 20, which may be configured and constructed to accept any type of roll or spool of covering, utilizing powered or idler rollers 21,22, powered by the hydraulic motor 46 which is driven by the hydraulic system 18. The rolling cradle 20 carries and lays out the bulk roll 24 (may also carry spools) of netting. To form the tower, a pole 26 is also mounted on the trailer 12 and supports a boom 28 at approximately a 90° angle. It should be understood that the tower be of such construction as to suspend the sweep over the row of crops and not limited to a particular angle. A guiding ring 30 is connected to the boom 28 to guide the netting 25 from the bulk roll 24, as seen in FIG. 1, into a sweep 32, also mounted on the boom 28, which guides and redirects the netting 25 90° (It should be understood that the sweep be of such construction as to direct the netting into alignment with the row of crops and not limited to a particular angle). As the netting 25 exits the sweep 32 it is then guided through a dispersement guide 34, which is also mounted to the boom 28. The dispersement guide 34 aids in the laying of the netting by spreading the netting from it's "roped" configuration as it exits the sweep 32 to a "fanned" configuration to cover the crops more effectively.
The preferred trailer 12 is as shown in FIG. 1. The trailer 12 should be a low profile trailer which may be towed between rows of crops. The trailer may be towed via a tractor 14 utilizing a standard hitch 16. The trailer's 12 purpose is carry the bulk roll 24 and facilitate laying of the netting. As such, the trailer is constructed to provide such a function. The trailer 12 (in this example a bin trailer) is preferably a heavy duty (steel) mobile (tires 37) frame 36 which may support a standard roll of netting, which can be approximately 200 to 1000 pounds. Preferably, the trailer should be able to support two rolls for dual dispersement/retrieval or just to have an extra roll when the first is completed.
The rolling cradle 20 can be mounted on a dedicated trailer or in a frame that is designed to attach to a standard 4-row vineyard/orchard trailer or a bin trailer. The purpose of the rolling cradle 20 is to support and rotate the bulk roll of netting 24. The cradle 20 consists of two parallel rollers 21,22, preferably PVC rollers, rotatively mounted at either end to a support frame 38, which is connected to or integral with the trailer 12. The support frame 38, preferably is a heavy duty metal of a welded tube type, Structural Grade, A-500-72 Gr. B. The forward and rear ends of the rollers 21,22 are rotatably connected, preferably via 11/2 inch stub axle and flange bearings, to T posts 40,41 in parallel fashion to receive a bulk roll of netting 24. Retaining posts 42,43 are also connected to the support frame 38 and aids in retaining the bulk roll 24 in place on the rollers 21,22 to prevent longitudinal sliding of the roll 24. Support rollers, 44, 47 (the right support roller 47 shown is shown in FIG. 8, and is a mirror image of support roller 44) are also mounted on posts which are mounted on frame 36 to support rollers 21,22, to prevent outward bowing of the rollers 21,22, under the weight of the bulk roll 24. The support frame 38 should be longitudinally adjustable to adapt to longer rollers 21,22 and bulk rolls 24.
The rollers 21,22 are preferably driven in a clockwise and counter clockwise direction, respectively, to rotate the bulk roll 24 to release the netting 25, by a close coupled orbital motor 46 with a pressure compensated flow control. A conventional hydraulic system 18 may be used to control the rotation from the tractor 14. Due to the great weight of a bulk roll 24, typically at least one of the rollers 21,22, or both in unison, or the bulk roll 24 itself, should be rotatably driven. Bearings may be incorporated to roll the rollers 21,22, driven merely by the drag of the netting 25 over the crops. The rolls may also be ground driven. The drive means may be constructed in other manners, as long as the bulk roll 24 may be controllably unrolled so as to not bind up or damage the crops. Conventional motors and hydraulic control systems are well known to achieve this task.
The support pole 26 is also vertically mounted on the trailer 12, frame 36, and preferably is a heavy duty metal of a welded tube type, Structural Grade, A-500-72 Gr. B. Also preferably, the tower 26 is round in shape to accommodate vertical adjustment of the boom 28, via a vertically adjustable mount/clamp 27, most preferably a sliding mount, upon which the boom is mounted.
The boom 28 as such is vertically slidably mounted on the support pole 26. The boom 28 extends substantially perpendicularly from the support pole 26 as well as from the direction of the trailer 12. The boom, as illustrated, supports the guidance elements (30, 32, 34) such that the netting may be laid from directly above the crops.
The guiding ring 30 is adjustably, preferably slidably, mounted on cross bar 48, via an adjustable mount/clamp 49. The cross bar is in turn connected to the boom 28, preferably slidably/adjustably along the length of the boom 28. The guiding ring 30 is not only adjustable along the length of the cross bar 48, but also adjustable around the axis of the cross bar 48. As stated above, the guiding ring 30, aids in collecting and directing the netting 25 into the sweep 32.
The sweep, or collector tube, 32, as seen in FIGS. 1-3, is essentially a guiding tube made of any rigid material, preferably steel having a plastic wear liner. The netting 25 is fed into the sweep 32 and is rerouted by about 90° to align the netting 25 with the rows of crops. The sweep, as seen in FIGS. 1-3, comprises a curved tube 32 having a conduit 50 therethrough and an entry end 52 and an exit end 54. The tubing is curved in about a 90° angle, or at an appropriate angle as mentioned above, and is supported by a support bar 56, which is secured to the tubing 32 at the entry end 52 and at the exit end 54. The support bar 56 is connected to an additional cross bar 58 which is mounted in a double adjustable mount/clamp 60 which allows for adjustable/slidably movement along both the cross bar 58 and the boom 28. The sweep 32 may, at its entry end 52, or at both ends, a periphery washer-like ring or trumpet-like configuration to aid in the feeding of the netting 25 into the sweep 32. When the netting passes through the sweep it ropes down to a narrow configuration and as a result becomes abrasive. As such, the sweep should be lined or at least have a protective insert at the entry end of the sweep. Preferably, the sweep 32 is steel having a Ultra High Molecular Weight (UHMW) polyethylene insert 62 to prevent wear on the sweep 32 and on the netting 25, as shown in FIGS. 2-3. The insert 62 comprises a trumpet-shaped interior conduit 64, a stepped-up rim 66 and an engagement portion 68 which snugly fits within the entry end 52 of the sweep 32. The insert 62 prevents wear of both the sweep 32 and the netting 25 itself. To further protect the netting, an inside liner with a low coefficient of friction may also be incorporated to line the fill length of the sweep conduit 50.
After the netting has been rerouted and exits the sweep 32, it is allowed to fan out/disperse and is guided over the crop rows by the dispersing guide 34. The dispersing guide 34 is mounted on a third crossbar 70 which in turn is slidably secured to the boom 28 via a second double adjustable mount/clamp 61 which allows for adjustable/slidably movement along both the cross bar 70 and the boom 28. The arcuately-shaped dispersing guide (elongated kidney-shaped guide) is further illustrated in FIGS. 4-5. As can be seen, the arc of dispersing guide 32 is preferably and substantially in a vertical plane and has a supporting cross bar 72 connecting the ends of the dispersing guide. Preferably, the supporting cross bar 72 has a securing post 74 extending from the cross bar 72 inwardly in relation to the arc of the dispersing guide 34 and adjustably and releasably mounted to the (may be welded thereto) cross bar 70 via an adjustable mounting brace 76, which perpendicularly is mounted on the end of the cross bar 70 (seen in phantom in FIG. 4). The securing post 74 may also be welded to the end of the cross bar 70 as seen in FIG. 1. The securing post 74 may also extend from the cross bar 72 outwardly in relation to the arc of the dispersing guide 34 and mounted on the end of the cross bar 70 as seen in FIG. 5, via a conventional mounting brace or via welding. Said mounting brace receives the securing post 74, as seen in FIG. 4, and is secured by tightening screws 73. The spread of the netting may be somewhat controlled by varying the size of the dispersing guide 34 and the acuteness of the curvature of the guide 34.
Preferably, before beginning laying netting over a particular row of crops, the end of the netting should be anchored at the starting end of the row. After the netting is initially unrolled from the bulk roll 24 and fed through the guide ring, the sweep and the dispersing guide, the end of the netting is gathered together and preferably bound, such as with duct tape (whipping). The end is then anchored by a secured body, such as a post 8 at the end of a crops row 9, as illustrated by FIG. 6. The anchoring of the end of the netting allows for tension in order to achieve a smooth, secure covering of the crops.
FIG. 7 further illustrates a rear view of the working apparatus and how the apparatus of the present invention smoothly and efficiently covers the row of crops as the tractor tows the trailer between the rows. Notice should be made to the numerous amount of adjustable elements incorporated in the device such that the height and width of the rows can be accounted for.
FIG. 8 still further illustrates a top view of the working apparatus.
The system illustrated above in FIGS. 1-8 can also be modified to accept and disperse other various holders or carriers of protective covering materials, such as smaller rolls or spools. The cradle need only be designed to allow the carrier to unroll at a controlled rate such that the protective covering is evenly dispersed onto the row of crops without creating too much or too little tension. For example, for smaller bulk rolls and spools a smaller cradle system may be used or, if the carrier incorporates a bore, as with conventional spools, a support may be constructed on the frame to suspend the carrier so that it may freely unroll or unroll in a controlled manner in cooperation with the speed of the tractor, such as with a hydraulically controlled rotation system, similar to the system mentioned above. In any case, by carrying the carrier on the trailer, low to the ground and feeding the protective covering up through the tower/sweep arrangement, better and safer control may be maintained.
FIGS. 9-13 illustrate the protective covering retrieval system 100, specifically the method and apparatus for retrieving the netting after it has been laid for disposal or to reuse in a reverse manner. Generally, this system consists of a hydraulically driven arbor shaft that accepts spools for retrieving netting for reuse or disposal. The shaft is mounted into a frame that is then hitched to a tractor. The netting is retrieved evenly onto plastic spools for reuse at a later time or onto the permanent spool that facilitates disposal in tightly compacted rolls. Netting is pulled off the vine row utilizing the same tower and sweep arrangement used in the above mentioned bulk roll laying system. This tower arrangement is manipulated over the rows of crops by attaching it to the same frame that carries the retrieval head.
Referring to FIG. 9, the tractor 114 carries a three point implement, herein referred to as trailer 112, via a standard hitch 111, preferably a category II 3-point mount, in such a manner by which the trailer 112 may be suspended slightly above ground during movement. The trailer 112 comprises a frame 113 which supports a level wind system 115 which receives spools 116 for retrieving the netting 125 in an even, tight package. The frame 113 also supports a deck/screen 118 to hold empty or full spools or rolls of wound netting for disposal. For the tower, a vertical support pole 120, which is also supported by the frame 113, in turn supports a boom 122 and an angled sweep 132 (preferably a 4-inch EMT (electrical metallic tubing) 90° Sweep with a UHMW wear liner). As the tractor moves forward between the rows, the netting is lifted from off the row of crops, through the sweep and reeled evenly onto a spool. Each element of this system is discussed separately and in more detail below.
The trailer 112 comprises a frame 113, which is a welded tube type structure, preferably structural grade, A-500-72 Gr. B. As mentioned above, the trailer is coupled to the hitch of the tractor, preferably via a category II 3-point mount which allows the driver to raise the frame when in motion and lower the frame 113 when idle.
The level wind system 115 and the raising and lowering of the frame is driven by a conventional tractor and tractor auxiliary hydraulics, both of which are well known. As shown in FIG. 9, the rear of the frame 113 forms a deck or screen 118 to hold empty or full spools or rolls of wound netting for disposal. The frame 113 also comprises skids 124 which support the frame when at rest.
The frame 113 further supports a mounting bracket standard 126, which is vertically mounted thereon. The support pole 120, which is similarly discussed above, is vertically mounted on the bracket standard via adjustable clamp 128. The support pole 120 may be vertically adjusted by loosening and tightening the adjustable clamp 128.
A boom 122 is horizontally mounted to the support pole 120 via an adjustable T clamp 133. The T clamp 133 may be loosened or tightened to adjust the length of the boom 122 on either side of the T clamp 133. As shown in FIG. 9, the boom 122 supports the sweep 132. The sweep 132 is basically configured as described above in the net laying system, except that it is reversed in its direction. The entry end 152 (the gathering fairlead) faces the crops, from which the netting is drawn, and the exit end 154 faces the level wind system 115, to which the netting is retrieved. Otherwise, the sweep 132 is attached to the boom 122 as discussed above in the net laying system.
The frame 113 also supports a level wind system 115 which is hydraulically actuated via a chain drive and incorporates a mounted rotating shaft, an oscillating linear actuator and removable PVC wear guides. The drive system which rotates the spools is preferably a close coupled orbital motor with down stream pressure sensing flow control which may be controlled through the tractor's hydraulic system by the driver.
FIG. 10 shows a more detailed view of the level wind system mechanism 115. In this embodiment, the netting is reeled onto a permanent spool 116, which is preferably constructed from formed and welded 12 gage HR steel, having a bolt on flange mount 117 for attachment to the arbor shaft 166. The bolt on flange mount 117 secures the spool 116 the arbor shaft 166 and is further illustrated in FIGS. 10a and 10b. The bolt on flange 117 is welded to the arbor shaft and bolted to the spool 116 The level wind system comprises a level wind housing 140 mounted upon the frame 113, wherein the level wind housing 140 is preferably in the configuration of an upside down L (herein referred to as short leg of the L 146 and long leg of the L 148) such that the loaded spool 116 is facially exposed the exit end of the sweep to best receive the gathered netting 144. The short leg 146 has a secured access lid 147 and houses a levelwind axle 156 and a level wind follower 154 which oscillates back and forth along the level wind axle 156. A guide 158, preferably a pair of parallel rods which are preferably tubular, are connected at one end to the levelwind follower 154 and extend at an angle downward across the open face of the spool 116 as shown in FIG. 10. The guides 158 oscillate back and forth across the face of the spool 116 allowing for even reeling of the gathered net 144, which travels between the pair of rods of the guide 158. The levelwind axle 156 is coupled to a levelwind driven sprocket 160, which in turn is driven by a levelwind belt 162 which communicates the levelwind driven sprocket 160 in motion with a levelwind drive sprocket 163 which is driven by an orbit motor 164. The orbit motor 164 also drives the spool axle 166 which in turn rotates the spool 116. As mentioned above, the motor 164 is preferably hydraulically powered, and, in this particular embodiment a selector valve 168 is mounted on the outer surface of the long leg 148 to regulate the hydraulic system and as such, the speed of the orbit motor 164. Since the orbit motor 164 drives both the rotation of the spool 116 and the levelwind follower 154, they move in cooperation to evenly reel the netting.
FIGS. 11-13 illustrate in a more detailed fashion the two part permanent spool 116 and the reeled gathered netting 170. As shown in FIGS. 11-12, the spool 116 has basically two parts, a distal half 172 and a proximal half 174, both having a bore 176 therethrough to accept the axle 166. Both halves, as illustrated, have truncated cone portions 178,180, a flange 182,184 on the base of the cones and a flat top portion 186,188. To secure the cone portions 178,180 on the axle 166 to form the spool 116, a locking lug 190 is provided in the distal half 172. The locking lug 190 has a locking lug lever 192 at its proximal end and extends through a bore 194, which is substantially parallel to bore 176, protruding from the flat top portion 186. At the distal end of the locking lug there is provided a key portion 196. As the distal half cone 172 is slid onto axle 166, the key portion is accepted by a locking lug hole 198 provided in the flat top portion 188 of the proximal half spool 174. To lock the two half spools together, lever 192 is merely turned around the axis of the locking lug 194. To maintain the lock, a spring loaded locking means may be provided to maintain the tension on the lever 192.
FIG. 13 shows a wound netting 170 after being removed from the temporary (trash) spool 116. The netting at this point is wound in a neat bundle 170 and may be disposed of or stored. As mentioned above, the ends of the netting may be bound to form a whipping 200, and may be tagged and stored for a particular row when wound upon a reusable spool.
Conventional spools may also be mounted and secured on the levelwind system in place of the permanent spool and secured in place. The netting may be retrieved in the same manner as discussed above with regard to the permanent spool. This method provides a wound length of netting loaded onto a reusable spool which may be stored for later use. Preferably, the spool is a conventional plastic spool having a hollow core with retaining flanges with the appropriate core length and flange diameter to match the amount and type of material retrieved to the carrying capacity of the operator, i.e., 50-70 pounds. The core diameter should be large enough to snugly fit the arbor shaft mentioned above. Such spools include an Andros Engineering Agri-Spool II which may be obtained from Andros Engineering, located in San Margarita, Calif.
These reusable loaded spools may also be loaded onto the levelwind mechanism on the arbor shaft after the permanent spool has been removed and the netting may be laid out over the crops by utilizing the same retrieval head, frame, tower and sweep arrangement used for retrieving. The valving to the shaft's drive motor can be manipulated to allow the motor to freewheel and the levelwind head is disengaged. The netting is pulled off the freewheeling spool, fed into the entry end of the reversed sweep and over the row of crops, driven merely by the tension created by the anchor and crops. For dispersal, loaded reusable spools may be seated on the above mentioned cradle or just a single axle mounted on the trailer.
FIGS. 14-15 illustrate a redistribution system 208 an alternative system of spooled roll layout, wherein the reusable spools of wound netting 170 are taken from storage and reused by unrolling them onto the rows of crops 205. The system is basically the same as that of the retrieval system except that the spool of wound netting is mounted on the tower rather than the sweep. Such a system is shown in FIG. 14.
As seen in FIG. 14, the reusable spool of wound netting, or distribution spool, 210 is mounted on the boom 122 and is allowed to unroll under the tension created by the dragging over the crops and primarily from the anchored end of the netting, as discussed above. A brake 212 may also be incorporated to prevent over spinning of the spool 210 so as to provide for a smooth laying of the netting.
FIG. 15 illustrates in more detail the distribution spool 210 and its mounting to the boom 122. As is conventional, the spool 210 comprises a spool drum 220 having a conduit therethrough and two retaining flanges 222. The distribution spool 210 is mounted onto an axle 224, shown in phantom, flush with an axle housing 226 from which the axle 224 extends. The axle extends through the axle housing 226 and is coupled with a brake drum 228. The distribution spool 210 is secured on the axle 224 via a retainer means 230, such as a clamp or a pin, such as a lynch pin. The spool is connected to the boom 122 via a cross bar 132 which is affixed to the axle housing 226 at one end and the boom 122 at the other end via a slidably adjustable clamp 234. The brake 212 comprises a brake belt 236 wrapped around the brake drum 228 and a tension spring 238 secured at one end to the brake belt 236 and to an anchor post 240, which is mounted on the cross bar 232, at the other end. The tension spring 238 provides sufficient tension to prevent the spool 210 from over-spinning and releasing netting prematurely, but is loose enough to prevent tearing of the netting and damage to the crops.
For each embodiment disclosed above, a modification may be made to provide for dual retrieval or layout systems on one trailer, such that the row of crops on either side of the tractor can be covered. In the case of the layout system for bulk rolls, a two row machine may be configured such that netting may be laid on two rows of crops. In such an embodiment, the rolls would be offset to the outside of the trailer with a common center column supporting opposing outrigger arms. Netting would be applied simultaneously to the rows immediately adjacent to the left and right sides of the trailer. FIG. 16 illustrates the manner in which two booms 28,28a may be mounted on the support pole 26 to allow for mirror images of the netting laying system. The collar 250 may be drilled at a 90° angle to allow for pin 252 securement in two positions for the booms for transport and for work. A thrust collar 254 keeps the booms in position on the support pole 26 also when switching from transport to work positioning. The systems of FIGS. 9 and 14 may also be set up in mirrored configuration to retrieve and layout netting from/on two rows of crops.
It should also be known that the above mentioned spools used for retrieval, the temporary spools or the reusable spools, may incorporate, preferably somewhere on the drum area of the reusable spool or the conical portion of the temporary spool, a snag, a hole or some kind of device to pinch or anchor the leading end of the covering when initially starting the winding operation so as not to have a laborer's hands caught in the spool.
The above mentioned hydraulically controlled drives of the different embodiments may be controlled by the operator of the tractor so that he may coordinate the speed of rotation of the rolls or spools during dispersement or retrieval of the protective covering with the speed of the tractor to prevent excessive tension of slack in the covering. This usually requires the operator to periodically look back at the trailer. Alternatively, a second operator may ride along on the trailer to control the speed of the roll or spool. Such hydraulic controls are well known in the field of agricultural implements.
This completes the description of the preferred and alternate embodiments of the invention. Those skilled in the art may recognize other equivalents to the specific embodiment described herein which equivalents are intended to be encompassed by the claims attached hereto.
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The present invention provides improved implements and methods for dispensing and retrieving protective crop covering materials (PCCM) onto/from rows of crops, particularly vineyard crops, to protect the plants from nuisance birds and weather conditions which cause damage to the crops. Basically, there is disclosed herein a system for layout of PCCM from a bulk roll of PCCM onto crops, a system for retrieving the PCCM from the crops and disposing it or storing said PCCM on reusable spools and a system for layout of the PCCM from the reusable spools.
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REFERENCE TO PENDING APPLICATIONS
[0001] This application is not based on any pending domestic or international patent application.
BACKGROUND OF THE INVENTION
[0002] The present invention is generally directed toward a safety lancet, more specifically, toward an safety lancet having safety cap that will eliminate any chance of it being exposed and accidentally cause an injury in an un-intended application.
[0003] Diabetics must test for stat glucose levels up in order to determine whether or not they should administer insulin. The procedure involves drawing a drop of blood from the diabetic's finger, placing the drop of blood on a commercially available blood glucose test strip, and comparing the resulting color of the test strip with a standard chart to determine the blood glucose concentration.
[0004] In order to draw the need drop of blood, a lancet, a medical device with a very sharp and tiny pointed instrument, is used. Diabetic patients use these devices to prick on the tip of a finger to produce a very small amount of blood which can then be collected and tested for its sugar content. The prior art lancets have to be handled very carefully by patient or person. These lancets are exposed and can be dangerous to accidental pricks and injury. Further, after use, they have to be disposed in a specially designed collection container or risk exposure to cross-contamination to another person. Clearly, there is a need for an improved lancet.
BRIEF SUMMARY OF THE INVENTION
[0005] The present invention satisfies the needs discussed above. The present invention is generally directed toward a safety lancet, more specifically, toward a safety lancet having safety cap that will eliminate any chance of it being exposed and accidentally cause an injury in an un-intended application.
[0006] One aspect of the present invention discloses a hub assembly secured within a pen body. The hub assembly has a hub body and a series of grooves. A safety cap assembly is slidably connected to the hub assembly, such that is engages the different grooves depending on whether it is in a pre-use position or a post-use position. In the pre-use position, a cannula that is located on the hub assembly is exposed and is ready for use. In a post-use position, the cannula is cover, or otherwise shielded, from contact.
[0007] An adjustment cap is also disclosed. This adjustment cap allows for the cannula to extend through an opening therein. Once the blood has been drawn, the adjustment cap is removed. In so doing, it engages with the safety cap pulling it from a pre-use position to its post-use position.
[0008] Upon reading the above description, various alternative embodiments will become obvious to those skilled in the art. These embodiments are to be considered within the scope and spirit of the subject invention, which is only to be limited by the claims which follow and their equivalents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a prospective, cut-away view of an embodiment of the present invention
[0010] FIG. 2 is a cut-away view of an embodiment of the hub assembly of the present invention.
[0011] FIG. 3 is a side view of the embodiment of the FIG. 1 after use of an embodiment of the hub assembly of FIG. 2 .
[0012] FIGS. 4-6 are additional embodiments of the safety cap assembly of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The attached drawing demonstrates an embodiment of the present invention. It is to be understood that the invention is not limited in its application to the details of the construction and arrangement of parts illustrated in the accompanying drawings. The invention is capable of other embodiments and of being practiced or carried out in a variety of ways. It is to be understood that the phraseology and terminology employed herein are for the purpose of description and not of limitation.
[0014] As shown in FIG. 1 , an embodiment 10 of the present invention has a pen body assembly 20 having a hub end 22 having an opening 24 . A hub assembly 30 secured within the pen body opening 24 . The hub assembly 30 has a hub body 32 , a cannula 44 and a safety cap assembly 50 .
[0015] The hub body 32 has a cannula end 34 and a pen body end 36 . Further, the hub body 32 has a series of grooves, a cannula end groove 38 located proximate to the cannula end 34 , a pen body end groove 40 located proximate to the pen body end 36 and an intermediate groove 42 located between the cannula end groove 38 and the pen body end groove 40 .
[0016] A cannula 44 is secured to the cannula end 34 and extends away therefrom.
[0017] The safety cap assembly 50 is dimensioned such that is can slide along the outside of the hub body 32 . The safety cap assembly is shown as cylindrical in dimension. This is illustrative and other dimensions, such rectangular, can be used. The safety cap assembly 50 has a safety cap body 52 having an upper end 54 and a lower end 56 . A plurality of safety cap pulling hooks 58 are located near, or proximate, to the upper end 54 and extending outward. A plurality of prongs 60 extend away from the lower end 56 . Each of the plurality of prongs 60 have an anti-back hook 62 extend inward.
[0018] The anti-back hooks 62 are dimensioned to engage with the intermediate groove 42 when the safety cap assembly 50 is a pre-use position and to engage with the cannula end groove 38 when the safety cap assembly 50 is in a post-use position.
[0019] An adjustment cap 70 engages with the hub assembly 30 by being dimensioned to fit over the hub assembly 30 and allow a portion of the cannula to 44 to extend beyond the adjustment cap 70 through a cannula opening 72 . Further, the adjustment cap 70 has a plurality of adjustment cap pulling hooks 74 located its inter surface. These hooks 74 engage the safety cap pulling hooks 58 such that when the adjustment cap 70 is removed, the safety cap assembly 50 is moved from its pre-use position to its post-use position allowing safety cap body 52 to shield the cannula 44 .
[0020] Another embodiment of the present invention allows for the hub assembly 30 to be removably secured to the pen body assembly 20 . In this embodiment, the pen body includes a plurality of locking hooks 26 that engage with the pen body end groove 40 located within the hub body 32 .
[0021] The operation of the embodiment of the present invention involves assembling the safety cap assembly 50 onto the hub assembly 30 by sliding the safety cap body 52 over the hub body 32 until the anti-back hooks 62 engage with the intermediate groove 42 . The pen body end 36 of the hub assembly 30 is then secured within said pen body 20 . In one embodiment, locking hooks 26 within the pen body 20 engage with the pen body end groove 40 locking in hub assembly 30 in position.
[0022] A needle cap 48 is removed exposing the cannula 44 and is replaced with the adjustment cap 70 . The adjustment cap 70 is positioned such that the desired length of the cannula 44 extends through the cannula opening 72 located within the adjustment cap 70 .
[0023] Once the blood has been collected, the adjustment cap 70 is removed by pulling it away from the pen body 20 . The action of removing the adjustment cap 70 allows the adjustment cap pulling hooks 74 engage with the safety cap pulling hooks 58 . Due to the different resistance caused by the different angle and thickness of the various contact fields, the resistance of the adjustment cap pulling hooks 74 and safety cap pulling hooks 58 are greater than that of the anti-back hooks 62 and intermediate groove 42 but less than that of the pen body locking hooks 26 that are engaged with the pen body end groove 40 . This causes the anti-back hooks 62 to disengage from said intermediate groove allowing the safety cap body to slide along the hub body until it engages with the cannula end groove 38 . When this occurs, the adjustment cap pulling hooks 74 disengage from the safety cap pulling hooks 58 allowing the adjustment cap 70 to be released. The safety cap body 52 now extends beyond the cannula end 34 of the hub assembly 30 , essentially covering, or otherwise shielding the cannula 44 . Thus preventing any accidental contact.
[0024] While the invention has been described with a certain degree of particularity, it is manifest that many changes may be made in the details of construction and the arrangement of components without departing from the spirit and scope of this disclosure. It is understood that the invention is not limited to the embodiments set forth herein for purposes of exemplification.
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The present invention is directed toward a safety lancet having a safety cap slidably engaged with a hub having a cannula such that in a pre-use position the safety cap allows access to the cannula and in post-use position, the safety cap prevents access to the cannula.
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FIELD OF THE INVENTION
[0001] The present invention relates generally to the field of replacing portions of the human structural anatomy with medical implants, and more particularly relates to an expandable implant and method for replacing skeletal structures such as one or more vertebrae or long bones or portions thereof.
BACKGROUND
[0002] It is sometimes necessary to remove one or more vertebrae, or a portion of the vertebrae, from the human spine in response to various pathologies. For example, one or more of the vertebrae may become damaged as a result of tumor growth, or may become damaged by a traumatic or other event. Removal, or excision, of a vertebra may be referred to as a vertebrectomy. Excision of a generally anterior portion, or vertebral body, of the vertebra may be referred to as a corpectomy. An implant is usually placed between the remaining vertebrae to provide structural support for the spine as a part of a corpectomy. FIG. 1 illustrates four vertebrae, V 1 -V 4 of a typical lumbar spine and three spinal discs, D 1 -D 3 . As illustrated, V 3 is a damaged vertebra and all or a part of V 3 could be removed to help stabilize the spine. If removed along with spinal discs D 2 and D 3 , an implant may be placed between vertebrae V 2 and V 4 . Most commonly, the implant inserted between the vertebrae is designed to facilitate fusion between remaining vertebrae. Sometimes the implant is designed to replace the function of the excised vertebra and discs. All or part of more than one vertebrae may be damaged and require removal and replacement in some circumstances. It may also be clinically appropriate in some circumstances to remove only one or a part of one of the discs, D 1 -D 3 for example, and replace the disc or a portion of the disc with an expandable implant in a fusion procedure.
[0003] Many implants are known in the art for use in a corpectomy or fusion procedure. One class of implants is sized to directly replace the vertebra or vertebrae that are being replaced. Another class of implants is inserted into the human body in a collapsed state and then expanded once properly positioned. Expandable implants may assist with restoring proper loading to the anatomy and achieving more secure fixation of the implant. Expandable implants may be advantageous because they allow for a smaller incision when properly positioning an implant. Implants that expand from a relatively small height to a relatively tall height while providing good structural strength may be more particularly advantageous to minimize incision size. Implants that included insertion and expansion mechanisms that are narrowly configured may also provide clinical advantages. Effective implants should also include a mechanism for securely locking in desired positions, and in some situations, be capable of collapsing. Implants with openings at or near their ends may also be advantageous in some embodiments because they allow for vascularization and bone growth into or through the implant.
[0004] Expandable implants may also be useful in replacing long bones or portions of appendages such as the legs and arms, or a rib or other bone that is generally longer than it is wide. Examples include, but are not limited to, a femur, tibia, fibula, humerus, radius, ulna, phalanges, clavicle, and any of the ribs.
SUMMARY
[0005] One embodiment of the invention is an expandable medical implant for supporting skeletal structures. The expandable medical implant may include a base with a first end, a second end, and a cannula extending between the first and second ends along a length of the base. The expandable medical implant may also include a first post having a proximal end that travels within the cannula and a distal end that extends beyond the first end of the base, and a second post having a proximal end that travels within the cannula and a distal end that extends beyond the second end of the base. The proximal end of the first post of some embodiments is configured to interdigitate with the proximal end of the second post within the cannula along at least a portion of the length of the base.
[0006] An embodiment of the invention is a method of spacing apart vertebral bodies. The method embodiment includes providing an expandable medical implant. The expandable medical implant may have a base with a first end, a second end, and a cannula extending between the first and second ends along a length of the base. The provided expandable medical implant may also include a first post having a proximal end that travels within the cannula and a distal end that extends beyond the first end of the base, and a second post having a proximal end that travels within the cannula and a distal end that extends beyond the second end of the base. The provided expandable medical implant is capable of having a first height between the distal end of the first post and the distal end of the second post, and is capable of expanding to a second height between the distal end of the first post and the distal end of the second post that is greater than the first height. The method includes expanding the first post relative to the base and the second post relative to the base by translating the first and second posts in opposite directions in the cannula so that the medical implant has a second height greater than two times the first height.
[0007] Another embodiment of the invention is an expandable medical implant means for spacing apart vertebral structures. The embodiment includes a base having a first end, a second end, and a cannula extending between the first and second ends along a length of the base. The embodiment also includes a first post having a proximal end that travels within the cannula and a distal end that extends beyond the first end of the base, and a second post having a proximal end that travels within the cannula and a distal end that extends beyond the second end of the base. The embodiment additionally includes an expansion means for extending the first post relative to the base and the second post relative to the base in opposite directions in the cannula so that a second height defined by a distance between the distal end of the first post and the distal end of the second post is greater than two times a first height defined by a distance between the distal end of the first post and the distal end of the second post.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is an elevation view of a segment of a lumbar spine.
[0009] FIG. 2 is a perspective view of an expandable medical implant in a partially expanded state.
[0010] FIG. 3 is a cross-sectional view of the expandable medical implant of FIG. 2 .
[0011] FIG. 4 is a perspective view of the expandable medical implant of FIG. 2 with some components removed for illustrative purposes.
[0012] FIG. 5 is a cross-sectional view of the expandable medical implant of FIG. 4 .
[0013] FIG. 6 is a perspective view of the expandable medical implant of FIG. 2 with some components removed for illustrative purposes.
[0014] FIG. 7 is cross-sectional view of a perspective view of the expandable medical implant of FIG. 2 with some components removed for illustrative purposes.
[0015] FIG. 8 is a perspective view of an embodiment of a collar of some embodiments of the invention.
[0016] FIG. 9 is a perspective view of an embodiment of posts of some embodiments of the invention.
[0017] FIG. 10 is a cross-sectional view of a perspective view of the expandable medical implant of FIG. 2 with some components removed for illustrative purposes.
[0018] FIG. 11 is a perspective view of an embodiment of a collar of some embodiments of the invention.
[0019] FIG. 12 is a plan view of the collar of FIG. 11 .
[0020] FIG. 13 is an elevation view of an instrument embodiment.
[0021] FIG. 14 is an elevation view of an end of the instrument of FIG. 13 .
[0022] FIG. 15 is an elevation view of an instrument embodiment.
[0023] FIG. 16 is an elevation view of an end of the instrument of FIG. 15 with an end portion removed for illustrative purposes.
[0024] FIG. 17 is a perspective view on an end of the instrument of FIG. 15 .
[0025] FIG. 18 is a perspective view of an expandable medical implant in a partially expanded state.
[0026] FIG. 19 is a perspective view of the expandable medical implant of FIG. 18 with some components removed for illustrative purposes.
DETAILED DESCRIPTION
[0027] An expandable medical implant for supporting skeletal structures is illustrated in different views and with certain variations in FIGS. 2-12 , 18 and 19 . The expandable medical implant 1 shown in FIG. 2 includes a base 10 , a first post 100 and a second post 200 . The base 10 is illustrated with a core 20 , a first collar 21 , and a second collar 22 . The base 10 has a first end 11 and a second end 12 . A cannula 13 extends between the first end 11 of the base 10 and second end 12 of the base 10 along a length of the base 10 .
[0028] The core 20 illustrated in FIGS. 2-7 is a cylindrical body. A core of other embodiments could have a cross-sectional shape other than round. For example, the core could be oval, triangular, rectangular, square, an other polygonal or curved shape, or a combination of the shapes noted or other functional shapes. As seen in FIGS. 3-7 , the core 20 of the base 10 includes a separator 15 dividing a cross-section of the base 10 such that one or more portions of the first post 100 are divided from one or more portions of the second post 200 . In the illustrated embodiment, the separator 15 divides the cross-section of the base 10 into substantially quarter sections. Division into quarter sections may be advantageous in some embodiments because it allows for each of the first post 100 and the second post 200 to have a pair of symmetrical legs occupying opposite quarters of the base. The symmetrical legs are well-positioned to receive loads applied to the posts 100 , 200 without particular eccentricities being induced in the materials of the posts 100 , 200 . Additionally, the configuration provides relatively large amounts of material in each leg that are near the periphery of each of the posts 100 , 200 . Materials near the peripheries contribute to the ability of the posts 100 , 200 to resist loading as columns. In other embodiments, a cross-section of the base 10 may be divided into only two sections so that each post may include a maximum amount of material in a single element. Such an arrangement would minimize the amount of cross-sectional area occupied by a separator and therefore would allow for each post to be as large as possible in cross-section. In still other embodiments, the number of legs of each post may be increase to better distribute the load carried by the posts around a periphery of the base 10 , and as noted above, reduce eccentricities, and therefore loads, in the materials of the posts. In addition to approximate wedge sections of a circle as depicted in FIGS. 3 and 5 , legs of the posts may be of any functional shape, and the separator 15 may be configured to intervene between all or part of the posts. For example, and without limitation, legs of the posts may be formed with a tongue on one leg or post and a groove on the other leg or post, or the posts may be formed with male and female dovetail connections along their lengths that allow the posts to interconnect.
[0029] In some embodiments, the separator may not extend fully across an interior of the base 10 , but may merely be a portion of the separator 15 closest to a wall of the base 10 . These embodiments may include components that fit between portions of two or more posts, or the components may fit in one or more notches along a side of one or more posts to guide the posts relative to the base.
[0030] In some embodiments, the separator 15 is in close tolerance with one or both of the posts 100 , 200 to stabilize the posts 100 , 200 relative to the base 10 . A tolerance “T” is noted in FIGS. 3 and 5 . This close tolerance may provide one or both of guidance in dynamic operation of the posts 100 , 200 and lateral or other structural stability to the posts 100 , 200 in the cannula 13 of the base 10 . For example, and without limitation, the separator 15 may be sized to provide gaps or tolerances from 0.02 mm and 1 mm between the posts 100 , 200 and the separator 15 . Tolerances may be specified between the posts 100 , 200 and the separator 15 , between portions of the posts 100 , 200 , or between the posts 100 , 200 and other components of the device in various embodiments.
[0031] The base 10 shown in FIGS. 2 , 4 , 6 , and 7 has an opening 17 for receiving an actuating instrument. In some embodiments, the opening 17 includes threads for receiving threads from a portion of the actuating instrument. As illustrated, the opening 17 is a single hole. A single hole opening would function, with the actuating instrument of FIGS. 13 and 14 . However, in other embodiments, the opening 17 may include two or more holes. For example, an opening for receiving the actuating instrument depicted in FIGS. 15-17 includes a set of three holes. The base 10 may include holes in one or more sides of the base 10 . As shown in FIG. 7 , the opening 17 passes through the center of the base 10 to provide the opening 17 in opposite sides of the base 10 . In other embodiments, the base 10 may include a protrusion rather than a hole. An instrument may fit with the protrusion to align an actuating instrument on the expandable medical implant 1 .
[0032] In some embodiments, the base 10 includes the first collar 21 and the second collar 22 . The first collar 21 and the second collar 22 in the illustrated embodiments are configured to regulate motion of the first post 100 and the second post 200 respectively along the length of the base 10 . The first collar 21 of the illustrated embodiment is coupled to the core 20 of the base 10 by pins (not shown) that are fixed in holes 23 ( FIGS. 2 and 10 ) and pass through a groove 27 ( FIGS. 4 , 6 , and 7 ). The first collar 21 may be coupled to the core 20 by any effective device, including but not limited to, through retaining rings, set screws, or staking in the groove 27 . The first collar 21 is allowed to rotate about the core 20 as the pins travel in the groove 27 . The first collar 21 illustrated includes teeth 25 around its perimeter that are configured to receive an instrument for rotating the first collar 21 relative to a portion of the base 10 , such as the core 20 . For example and without limitation, the teeth 25 may receive one of the actuating instruments shown in FIGS. 13-17 .
[0033] The second collar 22 of the illustrated embodiment is coupled to the core 20 of the base 10 by pins (not shown) that are fixed in holes 24 ( FIGS. 2 , 8 , and 10 ) and pass through a groove 28 ( FIGS. 4 , 6 , and 7 ). The second collar 22 is allowed to rotate about the core 20 as the pins travel in the groove 28 . The second collar 22 may be coupled to the core 20 by any effective device, including but not limited to, through retaining rings, set screws, or staking in the groove 28 . The second collar 22 illustrated includes teeth 26 around its perimeter that are configured to receive an instrument for rotating the second collar 22 relative to a portion of the base 10 , such as the core 20 . For example and without limitation, the teeth 26 may receive one of the actuating instruments shown in FIGS. 13-17 .
[0034] For the illustrated embodiments, the first collar 21 and the second collar 22 may be turned simultaneously with an instrument. For example, the instrument of FIGS. 13 and 14 or the instrument of FIGS. 15-17 may be connected to the core 20 to simultaneously turn the first collar 21 and the second collar 22 . In the illustrated configuration, the first collar 21 and the second collar 22 would be turned in opposite directions by either of the instruments of FIGS. 13-17 . However, because the first collar 21 and the second collar 22 have identical thread patterns, but are turned proximal end to proximal end, rotating them in opposite directions results in the first post 100 and the second post 200 moving together simultaneously and moving apart simultaneously. Any other operable combination of thread patterns and gears is also contemplated under embodiments of the invention. For example and without limitation, an actuating instrument may only have two intermeshing gears so that collars above and below would be moved in the same, rather than opposite, rotational directions. This configuration could be operable in conjunction with collars that have opposite thread patterns, for example, one with right-hand threads and one with left-hand threads.
[0035] Embodiments of the first post 100 and the second post 200 are illustrated in FIGS. 2 , 4 , 9 , and 10 . The first post 100 has a proximal end 101 and a distal end 102 . The proximal end 101 travels within the cannula 13 , and the distal end 102 extends beyond the first end 11 of the base 10 . As illustrated, the first collar 21 is coupled to the first post 100 by threads 121 ( FIGS. 7 and 10 ) such that motion of the first post 100 along the length of the base 10 is induced by rotation of the first collar 21 .
[0036] The second post 200 has a proximal end 201 and a distal end 202 . The proximal end 201 travels within the cannula 13 , and the distal end 202 extends beyond the second end 12 of the base 10 . As illustrated, the second collar 22 is coupled to the second post 200 by threads 122 ( FIGS. 7 , 8 , and 10 ) such that motion of the second post 200 along the length of the base 10 is induced by rotation of the second collar 22 .
[0037] The separator 15 of some embodiments also contributes toward preventing the threads 121 , 122 of the collars from disengaging with the respective posts 100 , 200 . Turning forces that create work along the threads may generate resulting forces that tend to push the posts 100 , 200 toward the center of the base 10 as forces are applied to the threads. The separator 15 may contact generally opposite sides of the respective posts 100 , 200 to counteract the resulting forces and allow the threads 121 , 122 of the collars to remain engaged with the posts 100 , 200 .
[0038] FIGS. 9 and 10 illustrate the proximal end 101 of the first post 100 interdigitated with the proximal end 201 of the second post 200 . The proximal end 101 of the first post 100 interdigitates with the proximal end 201 of the second post 200 within the cannula 13 along at least a portion of the length of the base 10 in some embodiments. The term interdigitate and variations of the term used herein refer to components that mesh together, intermingle, or overlap along their lengths. Components are considered to be configured to interdigitate when the components have a shape that will allow portions of the components to pass by one another and occupy a common cross-sectional plane along a length of the components. As applied to the embodiment illustrated in FIGS. 9 and 10 , the first post 100 is configured to interdigitate with the second post 200 because legs 111 , 112 of the first post 100 are shaped to fit in a common cross-sectional plane with legs 211 , 212 of the second post 200 along a length of the first and second posts 100 , 200 . More particularly for the illustrated embodiment, the first post 100 and the second post 200 each include two opposing, interdigitating legs 111 , 112 , and 211 , 212 . Each illustrated leg 111 , 112 , 211 , 212 is located substantially at a quarter point of a cross-section of the base 10 . In other embodiments, there may only be two legs such that each post 100 , 200 includes a maximum amount of material to the exclusion of separator components, as noted above. Some embodiments of the posts may include more than two pairs of interdigitating legs that distribute the load carried by the posts around a periphery of the base to reduce loading eccentricities, and therefore stresses in the materials of the posts.
[0039] One or both distal ends 102 , 202 of the posts 100 , 200 may include end pieces or shoes that connect with respective adjacent vertebral bodies. The shoes may include features that add an angled configuration to the distal ends 102 , 202 so that an implant will match or alter a lordotic, kyphotic spinal curvature or a curvature resulting from scoliosis. Alternatively or in addition, the shoes may include features that enhance connection to a vertebra. For example and without limitation, the shoes may include teeth, spikes, fasteners, openings, knurling, roughened surfaces, or any surface treatments or additional materials that are effective to enhance connection to a vertebra.
[0040] Another embodiment of a collar is illustrated in FIGS. 11 and 12 . A collar 222 is shown that may be substituted on either or both ends of the core 20 . The collar 222 may by coupled to the core 20 of the base 10 by pins (not shown) that are fixed in holes 224 and pass through either of the grooves 27 , 28 ( FIGS. 4 , 6 , and 7 ). The collar 222 is allowed to rotate about the core 20 as the pins travel in the grooves 27 , 28 . The collar 222 may be coupled to the core 20 by any effective device, including but not limited to, through retaining rings, set screws, or staking in the grooves 27 , 28 . The collar 222 illustrated includes teeth 226 around its perimeter that are configured to receive an instrument for rotating the collar 222 relative to a portion of the base 10 . For example and without limitation, the teeth 226 may receive one of the actuating instruments shown in FIGS. 13-17 .
[0041] The first post 100 with distal end 102 and proximal end 101 that travels within the cannula 13 may be configured to couple with the collar 222 through engagement mechanisms 250 . The engagement mechanisms 250 are disposed around one or more segments of an interior diameter of the collar 222 . When the collar 222 is in a first rotational position where the engagement mechanisms 250 do not interact with threads on the first post 100 , movement of the first post 100 along the base 10 is allowed. When the collar 222 is in a second rotational position where the engagement mechanisms 250 couple with threads on the first post 100 , movement of the first post 100 along the base 10 is restricted. For the illustrated collar 222 , the rotational movement between the first rotational position and the second rotational position is approximately 90 degrees. The collar 222 and engagement mechanism 250 may be similarly employed at the second end 12 of the base 10 in combination with the second post 200 . In other embodiments where one or both of the threads of the post or the segments of engagement mechanisms 250 are sized differently, the rotational movement between the first and second rotational positions would be changed proportionally. The engagement mechanisms 250 of the illustrated embodiment are threads that engage with threads of the respective posts. In other embodiments, expansion and collapse of the medical implant may be regulated by ratchet teeth or any other functional mechanism. Embodiments of the collar 222 with appropriate engagement mechanisms 250 would be equally effective with these other mechanisms and are contemplated under embodiments of the invention.
[0042] Another embodiment of the expandable medical implant is illustrated in FIGS. 18 and 19 . The expandable medical implant 1001 shown includes a base 1010 , a first post 1100 and a second post 1200 . The base 1010 is illustrated with a core 1020 , a first collar 1021 , and a second collar 1022 . The base 1010 has a first end 1011 and a second end 1012 . The illustrated core 1020 is generally cylindrical and includes openings for one or both of the first and second posts 1100 , 1200 to pass through the core 1020 . A cannula 1013 extends between the first end 1011 of the base 1010 and second end 1012 of the base 1010 along a length of the base 1010 . In FIG. 18 , the cannula 1013 is occupied by the first and second posts 1100 , 1200 . The base 1010 shown has an opening 1017 for receiving an actuating instrument. Configurations and functions of the opening 1017 and related structures are essentially similar to those describe in association with the opening 17 above.
[0043] The first collar 1021 and the second collar 1022 in the illustrated embodiment are configured to regulate motion of the first post 1100 and the second post 1200 respectively along the length of the base 1010 . The first collar 1021 is coupled to the core 1020 of the base 1010 by pins (not shown) that are fixed in holes 1023 ( FIG. 18 ) and pass through a groove (not shown) in the core 1020 . The first collar 1021 is allowed to rotate about the core 1020 as the pins travel in the groove. The first collar 1021 may be coupled to the core 1020 by any effective device, including but not limited to, through retaining rings, set screws, or staking in the groove. The first collar 1021 illustrated includes teeth 1025 around its perimeter that are configured to receive an instrument for rotating the first collar 1021 relative to a portion of the base 1010 , such as the core 1020 . For example and without limitation, the teeth 1025 may receive one of the actuating instruments shown in FIGS. 13-17 .
[0044] The second collar 1022 is coupled to the core 1020 of the base 1010 by pins (not shown) that are fixed in holes 1024 ( FIGS. 18 and 19 ) and pass through a groove (not shown) in the core 1020 . The second collar 1022 is allowed to rotate about the core 1020 as the pins travel in the groove. The second collar 1022 may be coupled to the core 1020 by any effective device, including but not limited to, through retaining rings, set screws, or staking in the groove. The second collar 1022 illustrated includes teeth 1026 around its perimeter that are configured to receive an instrument for rotating the second collar 1022 relative to a portion of the base 1010 , such as the core 1020 . For example and without limitation, the teeth 1026 may receive one of the actuating instruments shown in FIGS. 13-17 . Operation of the first and second collars 1021 and 1022 with actuating instruments is essentially similar to the operation of the first and second collars 21 , 22 described above.
[0045] Embodiments of the first post 1100 and the second post 1200 are illustrated in FIGS. 18 and 19 . The first post 1100 has a proximal end 1101 and a distal end 1102 . The proximal end 1101 travels within the cannula 1013 , and the distal end 1102 extends beyond the first end 1011 of the base 1010 . As illustrated, the first collar 1021 is coupled to the first post 1100 by threads such that motion of the first post 1100 along the length of the base 1010 is induced by rotation of the first collar 1021 .
[0046] The second post 1200 has a proximal end 1201 and a distal end 1202 . The proximal end 1201 travels within the cannula 1013 , and the distal end 1202 extends beyond the second end 1012 of the base 1010 . As illustrated, the second collar 1022 is coupled to the second post 1200 by threads such that motion of the second post 1200 along the length of the base 1010 is induced by rotation of the second collar 1022 . Because the second post 1200 has a smaller diameter than the first post 1100 , a threaded opening 1922 ( FIG. 19 ) in the second collar 1022 is smaller than a threaded opening 1911 ( FIG. 18 ) in the first collar 1021 . The pitch of the threads of the threaded openings 1911 and 1922 may be the same pitch, or a different pitch. Different pitches may be useful in some embodiments to cause different rates of travel for the first and second posts 1100 , 1200 in response to a common actuation. Different rates of travel may also permit greater overall expansion capacity by making a second post longer than a first post, since the longer second post would be able to nest through the center of the first post and extend all the way to a distal end of the first post. The longer second post may be expanded at a faster rate over its entire length and thereby give the implant a greater overall expansion distance.
[0047] As shown in FIG. 19 , the proximal end 1101 of the first post 1100 is interdigitated with the proximal end 1201 of the second post 1200 . As applied to the embodiment illustrated in FIGS. 18 and 19 , the first post 1100 is configured to interdigitate with the second post 1200 by receiving the second post 1200 within the inner diameter of the first post 1100 . The first and second posts 1100 , 1200 of the illustrated embodiment are tubular, round in cross-section, and threaded. However, in other embodiments, the posts may be oval, triangular, rectangular, square, an other polygonal or curved shape, or a combination of the shapes noted or other functional shapes. Various embodiments may or may not have threads, and may alternatively or in addition have ratchetings, notches, or other surfaces that may be engaged or gripped to move or hold the first and second posts.
[0048] A central bore 1190 is shown in FIGS. 18 and 19 . The central bore 1190 may extend completely or partially through one or both of the first and second posts 1100 , 1200 . The central bore 1190 may be filled in whole or in part with bone growth promoting substances, such as the substances detailed below. Bone growth promoting substance may be added to the central bore 1190 before implantation, during the expansion process of the implant, after the implant is implanted and fully expanded, or at any combination of the listed times.
[0049] Expandable medical implants under some embodiments are means for spacing apart vertebral structures. An expandable medical implant may include a base having a first end, a second end, and a cannula extending between the first and second ends along a length of the base; a first post having a proximal end that travels within the cannula and a distal end that extends beyond the first end of the base; and a second post having a proximal end that travels within the cannula and a distal end that extends beyond the second end of the base. Embodiments of the expandable medical implant may further include an expansion means for extending the first post relative to the base and the second post relative to the base in opposite directions in the cannula so that a second height defined by a distance between the distal end of the first post and the distal end of the second post is greater than two times a first height defined by a distance between the distal end of the first post and the distal end of the second post. In the illustrated embodiments, the first post 100 is a single component and the second post 200 is a single component. Consequently, in order for the expanded second height between the distal ends 102 , 202 to be greater than two times the first height, the first post 100 and the second post 200 interdigitate within the base 10 . In some embodiments, such as but not limited to the embodiment illustrated in FIGS. 18 and 19 , the first and second posts may interdigitate as concentric cylindrical cross-sections that extend from opposite ends of a base.
[0050] Actuating instruments 300 , 400 are illustrated in FIGS. 13-17 . The actuating instruments 300 , 400 are configured to operate with one or more collars 21 , 22 , 222 , 1021 , 1022 of some embodiments to regulate motion of the first post 100 , 1100 and the second post 200 , 1200 respectively along the length of the base 10 . As shown in FIGS. 13 and 14 , embodiments of the actuating instrument 300 include a single gear 301 with gear teeth 310 configured to engage with teeth 25 , 26 , 226 , 1025 , 1026 of one or more of the collars 21 , 22 , 222 , 1021 , 1022 . The actuating instrument 300 includes a tube 320 in which a shaft 330 is rotatably coupled. A gripping surface 325 may be applied to an exterior portion of the tube 320 . A handle 335 may be included on a proximal end of the shaft 330 for grasping to turn the shaft 330 relative to the tube 320 . The shaft 330 is coupled to the gear 301 . A tab 317 may be rotatably coupled in the opening 17 to secure the actuating instrument 300 to the base 10 while allowing the gear 301 to turn relative to the base 10 . The tab 317 of some embodiments may include a threaded portion to connect to a threaded area of the opening 17 , where the threaded portion rotates relative to the shaft 330 . In other embodiments, the tab 317 may include devices to expand or otherwise change shape to rotatably or fixedly connect with the opening 17 or other portion of the base 10 . As shown by arrow 305 in FIG. 14 , rotation of the gear 301 results in motion relative to the gear 301 at the top of the gear in a first direction and motion at the bottom of the gear in a second direction opposite from the first direction. This configuration may be useful with a device such as expandable medical implant 1 where this action results in counter-rotation of first collar 21 and second collar 22 and simultaneous movement of posts 100 , 200 toward a collapsed or expanded state. The diameter of the gear 301 may be altered in various embodiments to fit with implants with different distances G between gears ( FIG. 2 ).
[0051] As shown in FIGS. 15-17 , embodiments of the actuating instrument 400 include three gears 401 , 402 , 403 with gear teeth 411 , 412 , 413 . The gear teeth 412 , 413 are configured to engage with teeth 25 , 26 , 226 , 1025 , 1026 of one or more of the collars 21 , 22 , 222 , 1021 , 1022 . The actuating instrument 400 includes a tube 420 in which a shaft 430 is rotatably coupled. A gripping surface 425 may be applied to an exterior portion of the tube 420 . A housing 450 is coupled to the tube 420 in the embodiment shown. A tab 417 is coupled to the housing 450 . A handle 435 may be included on a proximal end of the shaft 430 for grasping to turn the shaft 430 relative to the tube 420 . The shaft 430 is coupled to the gear 401 . The tab 417 has three prongs in the illustrated embodiment and may be inserted in an opening in a base similar to the base 10 to secure the actuating instrument 400 to the base while allowing the gear 401 to turn relative to the base. The opening in which the actuating instrument 400 is inserted in the illustrated embodiment is similar to some embodiments of the opening 17 but includes holes for at least three prongs. One or more of the prongs of the tab 417 of some embodiments may include a threaded portion to connect to a threaded area of an opening. The tab 417 may include devices to expand, change orientation, or otherwise change shape to connect with a base or another portion of an implant. In FIG. 16 , an end portion of the housing 450 is shown removed for illustrative purposes. As depicted by arrow 405 in FIG. 16 , rotation of the gear 401 results in motion relative to the gear 401 at the top of the gear 401 in a first direction and motion at the bottom of the gear 401 in a second direction opposite from the first direction. The gear 401 meshes with and turns a gear 402 at the top of the gear 401 in a rotational direction depicted by arrow 406 . The gear 401 meshes with and turns a gear 403 at the bottom of the gear 401 in a rotational direction depicted by arrow 407 . This configuration may be useful with a device such as expandable medical implant 1 where this action results in counter-rotation of first collar 21 and second collar 22 and simultaneous movement of posts 100 , 200 toward a collapsed or expanded state. The diameter of the gears 401 , 402 , 403 may be altered in various embodiments to fit with implants with different distances G between gears ( FIG. 2 ) or to generate different amounts of mechanical advantage or relative rate of turning. For example and without limitation, the collars 21 , 22 , 222 , 1021 , 1022 may be more narrow top to bottom in some embodiments and create a greater distance G between gears of the collars. Rotation of the handle 435 of the actuating instrument 400 results in an opposite rotation of collars 21 , 22 , 222 , 1021 , 1022 compared with a like rotation of the handle 335 of the actuating instrument 300 . In still another embodiment, an actuating instrument (not shown) may include two gears so that rotation of the upper and lower parts of the instrument would be in a common direction. Such a rotation may be useful where upper and lower collars of an implant have opposite thread directions or for various other implant embodiments.
[0052] An embodiment of the invention is a method of spacing apart vertebral bodies. The method may include providing an expandable medical implant and expanding the implant so that the medical implant has an expanded height greater than two times the height of the implant or a component of the implant in an unexpanded state. For example expandable medical implants of the method may be capable of having a first height between a distal end of a first post and a distal end of a second post, and may be capable of expanding to a second height between the distal end of the first post and the distal end of the second post that is greater than the first height. The method may also include expanding the first post relative to the base and the second post relative to the base by translating the first and second posts in opposite directions in the cannula so that the second height is greater than two times the first height.
[0053] Referring to a non-limiting example, the expandable medical implant 1 has a base 10 with a first end 11 , a second end 12 , and a cannula 13 extending between the first end 11 and the second end 12 along a length of the base 10 . The illustrated first post 100 has a proximal end 101 that travels within the cannula 13 , and a distal end 102 that extends beyond the first end 11 of the base 10 . The illustrated second post 200 has a proximal end 201 that travels within the cannula 13 , and a distal end 202 that extends beyond the second end 12 of the base 10 . In the example, a first height is defined between the distal end 102 of the first post 100 and the distal end 202 of the second post 200 . The expandable medical implant 1 may be capable of expanding to a second height between the distal end 102 of the first post 100 and the distal end 202 of the second post 200 that is greater than the first height. The first post 100 of the illustrated embodiment is a unitary piece that does not telescope, fold out, or expand in any way with additional components beyond its distal end 102 . Likewise, the second post 200 of the illustrated embodiment is a unitary piece that does not telescope, fold out, or expand in any way with additional components beyond its distal end 202 . The diameters or lateral periphery of the proximal ends 101 , 201 of the posts 100 , 200 of the illustrated embodiment are approximately equal, thus giving the posts 100 , 200 approximately the same structural characteristics and load capacity.
[0054] Continuing with the present example, expanding the medical implant 1 includes expanding the first post 100 relative to the base 10 and the second post 200 relative to the base 10 . The expansion of the embodiment shown includes translating the first and second posts 100 , 200 in opposite directions in the cannula 13 so that the medical implant 1 has a second height that is greater than two times the first height. In some embodiments, the expansion distance may also be defined as expanding to a total height greater than two times the height of the base 10 . For the device shown, the first post 100 and the second post 200 are moved relative to the base 10 by rotating the collars 21 , 22 that are engaged with threads on the posts 100 , 200 . In particular, the collars 21 , 22 are rotated by inserting a tip of an instrument, such as either of the tabs 317 , 417 of the activation instruments 300 , 400 , into the base 10 and rotating the respective handles 335 , 435 of the instruments to turn one or more gears that mesh with the teeth 25 , 26 of the collars 21 , 22 . In other embodiments, either of the collars 21 , 22 may be independently turned to selectively control expansion from either end of the base 10 .
[0055] In an alternate embodiment, an expandable medical implant is expanded by attaching an expansion instrument to a distal end of a first post and a distal end of a second post. The expansion instrument may be of any variety capable of moving the distal ends away from one another. For example and without limitation, expansion instruments with mechanical linkages that react to spreading or compressing proximal components, screw driven devices, ratcheting devices, hydraulic, electrical, or other powered devices may be used to move the distal ends of the posts apart. Method embodiments include operating such an instrument to expand the expandable medical implant. Once expanded, the expandable medical implant may be locked into place by any effective mechanism. Non-limiting examples include locking with a pin, a set screw or other fastener, a locking ring, a clamp, an interference fit, and a collar. A more specific example of a collar is embodied in the collar 222 . Method embodiments may further include positioning the collar 222 is in a first rotational position where the engagement mechanisms 250 do not interact with threads on the posts 100 , 200 while the posts 100 , 200 are translated relative to the base 10 . When the posts 100 , 200 are moved to an acceptable position, the collar 222 may be moved to a second rotational position where the engagement mechanisms 250 couple with threads on the respective posts 100 , 200 , thus restricting movement of the posts 100 , 200 along the base 10 . As illustrated, the rotational movement between the first rotational position and the second rotational position is approximately 90 degrees. In other embodiments where one or both of the threads of the posts 100 , 200 or the segments of engagement mechanisms 250 are sized differently, the rotational movement between the first and second rotational positions would be changed proportionally.
[0056] Some embodiments may also include supplemental fixation devices as part of the expandable medical implant for further stabilizing the anatomy. For example, and without limitation, rod and screw fixation systems, anterior or lateral plating systems, facet stabilization systems, spinal process stabilization systems, and any devices that supplement stabilization may be used as a part of the expandable medical implant.
[0057] In some embodiments, the expandable medical implant may also include a bone growth promoting substance as part of or in combination with the expandable medical implant. All or a portion of the interior and/or periphery of the implant may be packed with a suitable bone growth promoting substance or therapeutic composition. For example, and without limitation, one or both of an end chamber 105 , 205 ( FIG. 2 ) may be filled with a bone growth promoting substance such as an osteogenic material to promote bone growth into the respective distal ends 102 , 202 of the expandable medical implant 1 . In other embodiments, a chamber may be created in a shoe to be placed on the end of a post, or a chamber may extend the entire length of the expandable medical implant that may be filled during or after expansion. The central bore 1190 shown in FIGS. 18 and 19 may be filled in whole or in part with a bone growth promoting substance. Bone growth promoting substances include, without limitation, autograft, allograft, xenograft, demineralized bone, synthetic and natural bone graft substitutes, such as bioceramics and polymers, and osteoinductive factors. A separate carrier to hold materials within the device may also be used. These carriers may include collagen-based carriers, bioceramic materials, such as BIOGLASS®, hydroxyapatite and calcium phosphate compositions. The carrier material may be provided in the form of a sponge, a block, folded sheet, putty, paste, graft material or other suitable form. The osteogenic compositions may include an effective amount of a bone morphogenetic protein (BMP), transforming growth factor β 1 , insulin-like growth factor, platelet-derived growth factor, fibroblast growth factor, LIM mineralization protein (LMP), and combinations thereof or other therapeutic or infection resistant agents, separately or held within a suitable carrier material. Placement may be accomplished directly or with the aid of an injection or transfer device of any effective type.
[0058] Embodiments of the implant in whole or in part may be constructed of biocompatible materials of various types. Examples of implant materials include, but are not limited to, non-reinforced polymers, reinforced polymer composites, PEEK and PEEK composites, shape-memory alloys, titanium, titanium alloys, cobalt chrome alloys, stainless steel, ceramics and combinations thereof. Reinforcing materials may include carbon, fiberglass, metal pieces, or any other effective reinforcing material. If a trial instrument or implant is made from radiolucent material, radiographic markers can be located on the trial instrument or implant to provide the ability to monitor and determine radiographically or fluoroscopically the location of the body in the spinal disc space. In some embodiments, the implant or individual components of the implant are constructed of solid sections of bone or other tissues. In other embodiments, the implant is constructed of planks of bone that are assembled into a final configuration. The implant may be constructed of planks of bone that are assembled along horizontal or vertical planes through one or more longitudinal axes of the implant. Tissue materials include, but are not limited to, synthetic or natural autograft, allograft or xenograft, and may be resorbable or non-resorbable in nature. Examples of other tissue materials include, but are not limited to, hard tissues, connective tissues, demineralized bone matrix and combinations thereof. Examples of resorbable materials that may be used include, but are not limited to, polylactide, polyglycolide, tyrosine-derived polycarbonate, polyanhydride, polyorthoester, polyphosphazene, calcium phosphate, hydroxyapatite, bioactive glass, and combinations thereof. Implant may be solid, porous, spongy, perforated, drilled, and/or open.
[0059] FIG. 1 illustrates four vertebrae, V 1 -V 4 , of a typical lumbar spine and three spinal discs, D 1 -D 3 . While embodiments of the invention may be applied to the lumbar spinal region, embodiments may also be applied to the cervical or thoracic spine or between other skeletal structures.
[0060] While embodiments of the invention have been illustrated and described in detail in the disclosure, the disclosure is to be considered as illustrative and not restrictive in character. All changes and modifications that come within the spirit of the invention are to be considered within the scope of the disclosure.
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Embodiments of the invention include expandable, implantable devices and methods. Devices expand linearly to provide secure fixation between or among anatomical structures. The expanded height of some embodiments is greater that twice the unexpanded height of the device. In some embodiments, an implant replaces one or more vertebral bodies of the spine.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to printers and printing methods. More specifically, the present invention relates to printers and printing methods for performing desired printing on print surfaces of three-dimensional print media.
2. Description of the Related Art
As a printer for performing printing on a print surface of a print medium, a “flatbed type” printer is conventionally known. A flatbed type printer includes: a table on which a print medium is placed; and a print head. All operations of the flatbed type printer are controlled by a microcomputer, so that the print head is displaced in two directions perpendicular to each other within the same plane, thus performing printing on the print medium placed on the table. Such a flatbed type printer is normally used to perform printing on a three-dimensional print medium having a flat print surface.
When printing is performed on a three-dimensional print medium using such a flatbed type printer, the three-dimensional print medium is placed at a given position on the table, and then printing is performed on the print surface of the print medium based on print data.
In order to perform printing at a given position on the print surface of the print medium, the print medium must be precisely placed at a predetermined position on the table. Therefore, the position at which the print medium is to be placed has to be precisely decided by, for example, measuring dimensions of the print medium in advance. As a result, the number of operational steps for performing printing on the print surface of the print medium is undesirably increased, which increases a burden on a worker.
As a solution to such a problem, a technique disclosed in JP 2007-136764 A, for example, is proposed. Specifically, JP 2007-136764 A discloses a technique for using a jig capable of holding a plurality of three-dimensional print media. The jig is fixable to a table. When printing is performed on the print media, a plurality of the print media are held by the jig, and the jig that holds the print media is fixed to the table. Note that a position at which each print medium is held by the jig is decided in advance. This position is input in advance to a microcomputer that controls a printer. The technique disclosed in JP 2007-136764 A is intended to position each three-dimensional print medium by the jig so as to perform printing at a given position on a print surface of the print medium.
However, the technique disclosed in JP 2007-136764 A makes it necessary to fabricate the jig in accordance with shapes and sizes of the print media, which means that the fabrication of the jig requires much time and trouble. Moreover, when the print media are produced in low quantities, this technique brings about an increase in cost.
SUMMARY OF THE INVENTION
Accordingly, preferred embodiments of the present invention provide a printer and a printing method which are capable of performing printing at a desired position on a print surface of a print medium without increasing a burden on a worker and without using a jig that holds the print medium.
A printer according to a preferred embodiment of the present invention is a flatbed type printer for performing predetermined printing based on print data. The printer includes a table that includes an upper surface on or over which a print medium including a flat print surface is to be placed, and that is movable at least in a Z-axis direction of an XYZ rectangular coordinate system which includes a Y-axis direction and the Z-axis direction; a print head disposed above the table and movable at least in an X-axis direction of the XYZ rectangular coordinate system which includes the X-axis direction and the Y-axis direction; a projecting unit configured to project a Gray code pattern on the table; an image taking unit configured to take an image of the Gray code pattern projected on the table by the projecting unit; a generating unit configured to generate a first spatial code image based on the image of the Gray code pattern taken by the image taking unit while the Gray code pattern is projected from the projecting unit, with the print medium not placed on or over the table whose upper surface is located at a given position in the Z-axis direction, and configured to generate a second spatial code image based on the image of the Gray code pattern taken by the image taking unit while the Gray code pattern is projected from the projecting unit, with the print medium placed on or over the table so that the print surface of the print medium is located at the given position; an image generating unit configured to generate an image of the print surface of the print medium by determining a difference between the first and second spatial code images; a normalizing unit configured to change an orientation the print surface to a given orientation in the image of the print surface of the print medium; and a converting unit configured to convert print data edited on the changed print surface into data printable on the pre-change print surface.
According to one preferred embodiment of the present invention, the table is preferably movable in the Y-axis direction and the Z-axis direction, and the print head is preferably movable in the X-axis direction.
According to one preferred embodiment of the present invention, the table is preferably movable in the Z-axis direction, and the print head is preferably movable in the X-axis direction and the Y-axis direction.
According to one preferred embodiment of the present invention, the normalizing unit is preferably configured to set a quadrilateral to an outline of the print surface and to calculate an orientation of the print surface so as to allow the print surface to assume the given orientation.
According to one preferred embodiment of the present invention, the projecting unit is preferably configured to project an 8-bit Gray code pattern.
According to one preferred embodiment of the present invention, the print head preferably is an inkjet head from which ink is ejected by an inkjet method.
A printing method according to yet another preferred embodiment of the present invention is a printing method for a flatbed type printer for performing predetermined printing based on print data, the printer including a table that includes an upper surface on or over which a print medium including a flat print surface is to be placed, and that is movable at least in a Z-axis direction of an XYZ rectangular coordinate system which includes a Y-axis direction and the Z-axis direction; a print head disposed above the table and movable at least in an X-axis direction of the XYZ rectangular coordinate system which includes the X-axis direction and the Y-axis direction; a projecting unit configured to project a Gray code pattern on the table; and an image taking unit configured to take an image of the Gray code pattern projected on the table by the projecting unit. The printing method includes steps of generating a first spatial code image using the image of the Gray code pattern taken by the image taking unit while the Gray code pattern is projected from the projecting unit, with the print medium not placed on or over the table whose upper surface is located at a given position in the Z-axis direction; generating a second spatial code image using the image of the Gray code pattern taken by the image taking unit while the Gray code pattern is projected from the projecting unit, with the print medium placed on or over the table so that the print surface of the print medium is located at the given position; generating an image of the print surface of the print medium based on the first and second spatial code images; changing an orientation of the print surface to a given orientation in the image of the print surface of the print medium; and converting print data edited on the changed print surface into data printable on the pre-change print surface.
According to one preferred embodiment of the present invention, the table is preferably movable in the Y-axis direction and the Z-axis direction, and the print head is preferably movable in the X-axis direction.
According to one preferred embodiment of the present invention, the table is preferably movable in the Z-axis direction, and the print head is preferably movable in the X-axis direction and the Y-axis direction.
According to one preferred embodiment of the present invention, the normalizing unit is preferably configured to set a quadrilateral to an outline of the print surface and to calculate an orientation of the print surface so as to allow the print surface to assume the given orientation.
According to one preferred embodiment of the present invention, the projecting unit is preferably configured to project an 8-bit Gray code pattern.
Various preferred embodiments of the present invention provide a printer and a printing method which are capable of performing printing at a desired position on a print surface of a print medium without increasing a burden on a worker and without using a jig.
The above and other elements, features, steps, characteristics and advantages of the present invention will become more apparent from the following detailed description of the preferred embodiments with reference to the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an explanatory diagram schematically illustrating a printer according to a preferred embodiment of the present invention.
FIG. 2 is an explanatory representation illustrating conversion of a checkered pattern captured by a camera into the number of pixels corresponding to a printer resolution, and projective transformation of an image taken by the camera into a reference coordinate system of a table.
FIGS. 3A and 3B are flow charts describing a procedure for performing printing by using the printer according to a preferred embodiment of the present invention.
FIG. 4A is an explanatory diagram illustrating a state in which an upper surface of the table is located at an initial position.
FIG. 4B is an explanatory diagram illustrating a state in which an upper surface of a base sheet is located at the initial position.
FIG. 4C is an explanatory diagram illustrating a state in which a print surface of a print medium is located at the initial position.
FIG. 4D is an explanatory diagram illustrating a state in which lines indicating regions arranged in a predetermined pattern are rendered on the upper surface of the base sheet.
FIG. 5A is an explanatory representation illustrating images each taken when a vertical Gray code pattern is projected on the base sheet with no print medium placed thereon, and a vertical spatial code image generated based on the taken images.
FIG. 5B is an explanatory representation illustrating images each taken when a horizontal Gray code pattern is projected on the base sheet with no print medium placed thereon, and a horizontal spatial code image generated based on the taken images.
FIG. 6A is an explanatory representation illustrating images each taken when a vertical Gray code pattern is projected on the print surface of each print medium with the print medium placed on the base sheet, and a vertical spatial code image generated based on the taken images.
FIG. 6B is an explanatory representation illustrating images each taken when a horizontal Gray code pattern is projected on the print surface of each print medium with the print medium placed on the base sheet, and a horizontal spatial code image generated based on the taken images.
FIG. 7A is an explanatory representation illustrating images obtained by projective transformation of print regions of the vertical and horizontal spatial code images without the print media into reference print regions.
FIG. 7B is an explanatory representation illustrating images obtained by projective transformation of print regions of the vertical and horizontal spatial code images with the print media into reference print regions.
FIG. 7C is an explanatory representation illustrating an image of the print surface of each print medium which is generated by using the images illustrated in FIGS. 7A and 7B .
FIG. 8A is an explanatory representation illustrating a state in which the images of the print surfaces of the print media are divided.
FIG. 8B is an explanatory representation illustrating a state in which a quadrilateral is set to an outline of each print surface in the image of the print surface of the print medium.
FIG. 8C is an explanatory representation illustrating a state in which an orientation of each print surface is normalized.
FIG. 9A is an explanatory representation illustrating a state in which the print surface is filled in with white.
FIG. 9B is an explanatory representation illustrating a state in which a quadrilateral is set to the outline of the print surface by using a rotating calipers method (rotating calipers algorithm).
FIG. 9C is an explanatory representation illustrating a state in which the orientation of the print surface is normalized.
FIG. 10A is an explanatory representation illustrating a state in which print data is edited on the normalized print surface.
FIG. 10B is an explanatory representation illustrating print data obtained by converting the print data of FIG. 10A into data printable on the pre-normalization print surface.
FIG. 10C is an explanatory representation illustrating print data obtained by converting the print data of FIG. 10A into data printable on the pre-normalization print surface.
FIG. 11 is an explanatory diagram schematically illustrating a printer according to an alternative preferred embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Hereinafter, preferred embodiments of a printer and a printing method according to the present invention will be described with reference to the accompanying drawings.
As used herein, the term “inkjet method” refers to a printing technique which is based on an inkjet technology using various conventionally known methods including various continuous methods such as a binary deflection method or a continuous deflection method and/or various on-demand methods such as a thermal method or a piezoelectric element method.
FIG. 1 is an explanatory diagram schematically illustrating a printer 10 . In the following description, the terms “right”, “left”, “up” and “down” refer to right, left, up and down when viewed from a worker present in front of the printer 10 , respectively. A direction toward the worker from the printer 10 is defined as a forward direction, and a direction away from the worker toward the printer 10 is defined as a rearward direction. The reference signs “F”, “Re”, “R”, “L”, “U” and “D” in the drawings represent front, rear, right, left, up and down, respectively. The reference sign “X” in the drawings represents an X axis, i.e., a right-left direction (main scanning direction). The reference sign “Y” in the drawings represents a Y axis, i.e., a front-rear direction (sub-scanning direction). The reference sign “Z” in the drawings represents a Z axis, i.e., a vertical direction. It is to be noted that the above directions are defined only for convenience of description and should not be construed as being restrictive. Also note that the term “main scanning direction” refers to a width direction of a three-dimensional print medium 200 (see FIG. 4C ), and the term “sub-scanning direction” refers to a direction perpendicular to the main scanning direction.
The printer 10 is a flatbed type inkjet printer. The printer 10 preferably includes a base member 12 , a table 14 , a rod-shaped member 16 , a movable member 18 , a print head 20 , a vertical member 22 , a projector 24 , and a camera 26 .
The base member 12 preferably includes guide grooves 28 a and 28 b that extend in a Y-axis direction (front-rear direction).
The table 14 is disposed on the base member 12 . The table 14 preferably includes an upper surface 14 a . The upper surface 14 a of the table 14 has a flat shape. The three-dimensional print medium 200 (see FIG. 4C ) is placed over the upper surface 14 a of the table 14 . The table 14 is movable in a Z-axis direction (vertical direction) within a given range by a moving mechanism (not illustrated). The table 14 is moved in the Z-axis direction, thus allowing the print medium 200 placed over the upper surface 14 a of the table 14 to be moved in the Z-axis direction. The range in which the table 14 is moved up and down corresponds to, for example, a range of a thickness of the print medium 200 on which printing can be performed by the printer 10 . The movement of the table 14 in the Z-axis direction is controlled by the moving mechanism (not illustrated) based on an input provided by a worker. Note that a conventionally known technique may be used for the moving mechanism for moving the table 14 in the Z-axis direction. A non-limiting example of this moving mechanism is a combination of a gear and a motor.
The movable member 18 preferably includes the rod-shaped member 16 and the print head 20 . The movable member 18 is moved in the Y-axis direction (front-rear direction) along the guide grooves 28 a and 28 b of the base member 12 by a moving mechanism (not illustrated). Note that a conventionally known technique may be used for the moving mechanism for moving the movable member 18 in the Y-axis direction (front-rear direction). A non-limiting example of this moving mechanism is a combination of a gear and a motor.
The rod-shaped member 16 extends in an X-axis direction (right-left direction). The rod-shaped member 16 moves in the Y-axis direction (front-rear direction) above the table 14 . A front surface of the rod-shaped member 16 is provided with a guide rail (not illustrated).
The print head 20 is an inkjet head from which ink is ejected by an inkjet method. The print head 20 performs printing on a print surface 200 a (see FIG. 4C ) of the print medium 200 placed over the table 14 . The print head 20 is provided at the rod-shaped member 16 . The print head 20 is movable along the guide rail (not illustrated) provided at the front surface of the rod-shaped member 16 . The print head 20 is provided with a belt (not illustrated) which is movable in the X-axis direction (right-left direction). The print head 20 is movable in the X-axis direction (right-left direction) with respect to the rod-shaped member 16 . The belt is wound by a moving mechanism (not illustrated), thus moving the belt so that the print head 20 is moved from left to right or from right to left in the X-axis direction. Note that a conventionally known technique may be used for the moving mechanism to move the print head 20 in the X-axis direction (right-left direction) by winding the belt. Examples of this moving mechanism include a combination of a gear and a motor.
The vertical member 22 is provided at a rear portion of the base member 12 . The vertical member 22 extends upward from the base member 12 .
The projector 24 is provided at the vertical member 22 . The projector 24 is fixed to the vertical member 22 . The projector 24 projects a Gray code pattern on the entire upper surface 14 a of the table 14 . The projector 24 projects a vertical 8-bit Gray code pattern on the upper surface 14 a of the table 14 . The projector 24 also projects a horizontal 8-bit Gray code pattern on the upper surface 14 a of the table 14 .
The camera 26 is provided at the vertical member 22 . The camera 26 is fixed to the vertical member 22 . The camera 26 is capable of taking an image of the entire upper surface 14 a of the table 14 in a direction different from a direction in which the projector 24 projects the Gray code pattern.
As illustrated in FIG. 4C , the print medium 200 preferably has a rectangular or substantially rectangular parallelepiped shape. The print surface 200 a of the print medium 200 has a flat shape. When the print medium 200 is placed over the upper surface 14 a of the table 14 , the print surface 200 a is horizontal or substantially horizontal. Note that the shape of the print medium 200 is not limited to a rectangular or substantially rectangular parallelepiped shape.
As illustrated in FIG. 1 , the printer 10 is communicably connected to a microcomputer 300 . All operations of the printer 10 are controlled by the microcomputer 300 . The microcomputer 300 preferably includes a spatial code image generator 50 , an image generator 52 , a normalizer 54 , and a converter 56 . The spatial code image generator 50 generates a spatial code image based on an image of the Gray code pattern which is taken by the camera 26 . Using the spatial code image generated by the spatial code image generator 50 , the image generator 52 generates an image of the print surface 200 a (see FIG. 4C ) of the print medium 200 . Using, as a given orientation, an orientation of the print surface 200 a in the image of the print surface 200 a generated by the image generator 52 , the normalizer 54 normalizes the print surface 200 a . The converter 56 converts print data, which is edited on the print surface 200 a normalized by the normalizer 54 , into data printable on the pre-normalization print surface 200 a.
The following description will be made on the assumption that the printer 10 performs desired printing on the flat print surface 200 a of the three-dimensional print medium 200 . First, in the printer 10 , a calibration of the camera 26 (which will hereinafter be referred to as a “camera calibration”), and a calibration between the camera 26 and the upper surface 14 a of the table 14 (i.e., a print coordinate system) are performed. Each of the calibrations is performed at a given time, e.g., at the time of shipment from a factory or at the time of replacement of the camera 26 .
The camera calibration is performed using a separate display device (e.g., a liquid crystal display) which is independent of the printer 10 . Specifically, in performing the camera calibration, an image of a checkered pattern is taken by the camera 26 at the maximum angle of view, and camera parameters are calculated using Zhang's method. In this preferred embodiment, as this checkered pattern, a checkered pattern displayed on the separate display device is used instead of a checkered pattern rendered on the upper surface 14 a of the table 14 . Note that a technique disclosed in JP 2007-309660 A, for example, is used for a method of calculating camera parameters by Zhang's method, and therefore, detailed description thereof will be omitted.
When the printer 10 is used, only internal parameters (A) of the camera, which include lens distortion coefficients (k 1 , k 2 ), are utilized by using Equations (1) and (2) calculated by Zhang's method.
Equation
1
s
m
~
=
A
[
R
T
]
M
~
(
1
)
Equation
2
{
u
⋓
=
u
+
(
u
-
u
0
)
[
k
1
(
x
2
+
y
2
)
+
k
2
(
x
2
+
y
2
)
2
]
v
⋓
=
v
+
(
v
-
v
0
)
[
k
1
(
x
2
+
y
2
)
+
k
2
(
x
2
+
y
2
)
2
]
(
2
)
After the camera calibration has been performed, the camera 26 is installed on the printer 10 , and a calibration to obtain a positional and orientational relationship between the camera 26 and the upper surface 14 a of the table 14 (i.e., the calibration between the camera 26 and the upper surface 14 a of the table 14 ) is performed. Specifically, in performing the calibration between the camera 26 and the upper surface 14 a of the table 14 , a matrix H c2p for projective transformation from an image taken by the camera into an image of a print region is calculated.
First, an image is taken, with nothing placed over the table 14 . In this case, as illustrated in FIG. 2 , a checkered pattern in which checkers are arranged in a given pattern is rendered on the table 14 . Next, using Equation (2), lens distortion of the taken image (i.e., the image of the checkered pattern rendered on the table 14 ) is corrected. Subsequently, checker intersection coordinates are estimated with sub-pixel precision. Then, as illustrated in FIG. 2 , the checkered pattern is converted into the number of pixels corresponding to a printer resolution, and the projective transformation matrix H c2p to transform the checker intersection coordinates into pixel coordinates is obtained.
Equation
3
s
[
x
p
y
p
1
]
=
H
c
2
p
[
x
c
y
c
1
]
,
H
c
2
p
=
[
h
11
h
12
h
13
h
21
h
22
h
23
h
31
h
32
h
33
]
(
3
)
Assuming that dimensions of each checker of the checkered pattern are defined as n (mm) and the printer resolution is defined as r (dpi), the number of pixels of each checker after the transformation is r×n/25.4. Then, n sets of image coordinate values obtained before and after the transformation are applied to Equation (3).
{
s
x
pn
=
h
11
x
cn
+
h
12
y
cn
+
h
13
s
y
pn
=
h
21
x
cn
+
h
22
y
cn
+
h
23
s
=
h
31
x
cn
+
h
32
y
cn
+
h
33
Equation
4
{
h
11
x
cn
+
h
12
y
cn
+
h
13
-
h
31
x
cn
x
pn
-
h
32
y
cn
x
pn
-
h
33
x
pn
=
0
h
21
x
cn
+
h
22
y
cn
+
h
23
-
h
31
x
cn
y
pn
-
h
32
y
cn
y
pn
-
h
33
y
pn
=
0
Equation
5
[
x
c
1
y
c
1
1
0
0
0
-
x
c
1
x
p
1
-
y
c
1
x
p
1
-
x
p
1
0
0
0
x
c
1
y
c
1
1
-
x
c
1
y
p
1
-
y
c
1
y
p
1
-
y
p
1
⋮
x
cn
y
cn
1
0
0
0
-
x
c
n
x
p
n
-
y
c
n
x
p
n
-
x
pn
0
0
0
x
cn
y
cn
1
-
x
cn
y
p
n
-
y
cn
y
p
n
-
y
pn
]
[
h
11
h
12
⋮
h
32
h
33
]
=
[
0
0
⋮
0
0
]
Equation
6
When this equation (Equation 6) is expressed as B·h=0, h is obtained as a right singular vector corresponding to the minimal singular value of B or a characteristic vector corresponding to the minimal characteristic value of B T B (for example, a function such as OpenCV 2.x or SVD::solvez( ) is utilized). Note that a conventionally known technique (see, for example, Gang Xu, “3D CG from Photographs”, Kindai Kagaku Sha), for example, is preferably used for the above-described calibration between the camera 26 and the upper surface 14 a of the table 14 , and therefore, detailed description thereof will be omitted.
Next, a printing procedure for performing printing on the print surface 200 a of the print medium. 200 by the printer 10 , in which the above-described camera calibration and calibration between the camera 26 and the upper surface 14 a of the table 14 have been performed, will be described with reference to FIGS. 3A and 3B .
First, in Step S 302 , a worker places a base sheet 30 on the upper surface 14 a of the table 14 of the activated printer 10 in a state where the movable member 18 is located directly below the vertical member 22 (see FIG. 4B ).
In this preferred embodiment, the state where the movable member 18 is located directly below the vertical member 22 means a state where a Gray code pattern can be projected onto the table 14 by the projector 24 without casting a shadow of the movable member 18 or the print head 20 on the table 14 , and the movable member 18 or the print head 20 is not captured when an image of the Gray code pattern is taken by the camera 26 . Note that if this state is created, the movable member 18 does not have to be located directly below the vertical member 22 .
In Step S 304 , the table 14 is moved downward by a thickness t 1 of the base sheet 30 . Specifically, the table 14 is moved downward so that an upper surface 30 a of the base sheet 30 is located at a position taken up by the upper surface 14 a of the table 14 at the time of the calibration (see FIGS. 4A and 4B ). Hereinafter, the position taken up by the upper surface 14 a of the table 14 at the time of the calibration will be referred to as an “initial position” as appropriate.
More specifically, when the thickness t 1 of the base sheet 30 is 2 mm, for example, the base sheet 30 is placed on the table 14 , the upper surface 14 a of which is located at the initial position, and then the worker moves the table 14 downward by 2 mm, for example. Note that the base sheet 30 preferably is an adhesive sheet, and therefore, the print medium 200 is not easily moved once the print medium 200 is placed on the upper surface 30 a.
In Step S 306 , the microcomputer 300 controls the printer 10 so that an 8-bit Gray code pattern is projected on the upper surface 30 a of the base sheet 30 from the projector 24 . The camera 26 takes an image of the projected Gray code pattern. The spatial code image generator 50 generates a spatial code image based on each image taken by the camera 26 .
Specifically, as illustrated in FIG. 5A , a vertical Gray code pattern, which is a Gray code pattern that has been vertically changed with respect to a print surface, is projected on the upper surface 30 a of the base sheet 30 from the projector 24 , and the camera 26 takes an image of the projected vertical Gray code pattern. The spatial code image generator 50 generates a vertical spatial code image without the print medium 200 based on each image taken by the camera 26 . Furthermore, as illustrated in FIG. 5B , a horizontal Gray code pattern, which is a Gray code patern that has been horizontally changed with respect to a print surface, is projected on the upper surface 30 a of the base sheet 30 from the projector 24 , and the camera 26 takes an image of the projected horizontal Gray code pattern. The spatial code image generator 50 generates a horizontal spatial code image without the print medium 200 based on each image taken by the camera 26 .
Upon acquisition of the vertical and horizontal spatial code images without the print medium 200 , the worker places the print medium 200 on the upper surface 30 a of the base sheet 30 in Step S 308 (see FIG. 4C ). In this case, the worker may roughly arrange a plurality of the print media 200 along the X-axis direction (right-left direction) and the Y-axis direction (front-rear direction). The print media 200 may be inclined to some extent with respect to the X axis or the Y axis. The plurality of print media 200 are arranged on the upper surface 30 a of the base sheet 30 so that the print media 200 adjacent to each other are located at intervals. More specifically, the plurality of print media 200 are disposed in regions arranged in a predetermined pattern on the upper surface 30 a of the base sheet 30 (see FIG. 4 d ). Note that the regions arranged in the predetermined pattern are stored in the microcomputer 300 . Lines (grid) 32 serving as boundaries of these regions are rendered on the upper surface 30 a of the base sheet 30 . Alternatively, marks may be rendered instead of the lines 32 .
After the print media 200 have been placed on the upper surface 30 a of the base sheet 30 , the worker operates the operator (not illustrated) in Step S 310 . Thus, the table 14 is moved downward by a thickness t 2 of each print medium 200 . In other words, the table 14 is moved downward so that the print surface 200 a of each print medium 200 is located at the initial position (see FIG. 4C ).
Specifically, when the thickness t 2 of each print medium 200 is 10 mm, for example, the print media 200 are placed on the upper surface 30 a of the base sheet 30 with the upper surface 30 a located at the initial position, and then the worker moves the table 14 downward by 10 mm, for example.
In Step S 312 , the microcomputer 300 controls the printer 10 so that an 8-bit Gray code pattern is projected on the print surface 200 a of each print medium 200 and the upper surface 30 a of the base sheet 30 from the projector 24 . The camera 26 takes an image of the projected Gray code pattern. The spatial code image generator 50 generates a spatial code image based on each image taken by the camera 26 .
Specifically, as illustrated in FIG. 6A , a vertical Gray code pattern is projected on the print surface 200 a of each print medium 200 and the upper surface 30 a of the base sheet 30 from the projector 24 , and the camera 26 takes an image of the projected vertical Gray code pattern. The spatial code image generator 50 generates a vertical spatial code image with the print media 200 based on each image taken by the camera 26 . Furthermore, as illustrated in FIG. 6B , a horizontal Gray code pattern is projected on the print surface 200 a of each print medium 200 and the upper surface 30 a of the base sheet 30 from the projector 24 , and the camera 26 takes an image of the projected horizontal Gray code pattern. The spatial code image generator 50 generates a horizontal spatial code image with the print media 200 based on each image taken by the camera 26 .
Upon acquisition of the vertical and horizontal spatial code images with the print media 200 , the image generator 52 generates an image of the print surface 200 a of each print medium 200 by combining the vertical spatial code image without print media and the horizontal spatial code image without print media and by combining the vertical spatial code image with print media and the horizontal spatial code image with print median Step S 314 .
In this preferred embodiment, the spatial code images generated in Step S 306 (i.e., the vertical and horizontal spatial code images without the print medium 200 ) and the spatial code images generated in Step S 312 (i.e., the vertical and horizontal spatial code images with the print media 200 ) have the same code value only at surfaces located at the initial position. The image generator 52 obtains a difference between the spatial code images generated in Step S 306 and the spatial code images generated in Step S 312 to extract the image of the print surface 200 a of each print medium. 200 , thus generating the image of the print surface 200 a of each print medium 200 .
Specifically, as illustrated in FIG. 7C , in an image “diff” of the print surface 200 a of each print medium 200 , a pixel i is presented in white or black based on the following equation:
diff
i
=
{
255
,
(
bu
i
-
mu
i
)
2
+
(
bv
i
-
mv
i
)
2
<
THRESH
0
,
otherwise
Equation
7
As illustrated in FIG. 7A , “bu” is an image obtained by performing projective transformation of only a print region selected from the vertical spatial code image without the print media. “bu i ” represents an ith pixel in the image “bu”. “bv” is an image obtained by performing projective transformation with the projective transformation matrix H c2p of only a print region, selected from the horizontal spatial code image without the print media, into a reference print region serving as a printable region on the upper surface 14 a of the table 14 . “bvi” represents an ith pixel in the image “bv”.
As illustrated in FIG. 7B , “mu” is an image obtained by performing projective transformation of only a print region selected from the vertical spatial code image with the print media. “mu” represents an ith pixel in the image “mu”. “mv” is an image obtained by performing projective transformation with the transformation matrix H c2p of only a print region, selected from the horizontal spatial code image with the print media, into the reference print region. “mv i ” represents an ith pixel in the image “mv”.
In Equation (7), “255” represents white. “0” represents black. THRESH is set to “2”, for example.
The print media 200 are disposed in the regions arranged in the predetermined pattern defined on the upper surface 30 a of the base sheet 30 . Therefore, in Step S 316 , the normalizer 54 divides the images of the print surfaces 200 a of the print media 200 , which have been generated in Step S 314 , in accordance with the predetermined pattern (see FIG. 8A ).
In Step S 318 , using a rotating calipers method (rotating calipers algorithm), the normalizer 54 sets a quadrilateral to an outline of each print surface 200 a in the image of the print surface 200 a of the print media (see FIG. 8B ). The normalizer 54 calculates the orientation and origin point of each print surface 200 a , and performs projective transformation of each print surface 200 a , thus normalizing each print surface 200 a so as to change the orientation of each print surface 200 a to a given orientation 200 b (see FIG. 8C ). As used herein, the term “given orientation” refers to, for example, an orientation in which each side of the print surface 200 a is parallel to the X axis or Y axis.
FIGS. 9A , 9 B and 9 C are explanatory representations illustrating a procedure for normalizing the orientation of the print surface 200 a . As illustrated in FIG. 9A , the normalizer 54 first fills in the print surface 200 a with white (=255). Specifically, the normalizer 54 sequentially searches for a pixel of black (=0) from an origin point A of the region for the print surface 200 a , sets, using the black pixel as a starting point, a region where the black pixels are continuous as white pixels (=255) in another image buffer of the same size, and then turns the black pixels white and vice versa. Although the origin point A of the region for the print surface 200 a is a point located at an upper left end of each of the regions arranged in the predetermined pattern in the present preferred embodiment, the location of the origin point A is not limited to this point.
Next, as illustrated in FIG. 9B , using a rotating calipers method, a quadrilateral is set to the outline of the print surface 200 a filled in with white. Note that this rotating calipers method is a conventionally known technique, and therefore, detailed description thereof will be omitted.
Then, a rotation matrix R is obtained. Using the rotation matrix R, a straight line H, connecting an upper left end point I of the quadrilateral and an upper right end point II of the quadrilateral, is made parallel to the Y axis. Assuming that an angle formed between the Y axis and the straight line H connecting the points I and II is θ, the rotation matrix R is represented as follows:
R
=
[
cos
θ
sin
θ
0
-
sin
θ
cos
θ
0
0
0
1
]
Equation
8
Using this rotation matrix R, coordinate values of four points of the quadrilateral, i.e., the point I, the point II, a lower left end point III and a lower right end point IV of the quadrilateral, are transformed. Subsequently, a translational transformation matrix T for moving the coordinates of the point I after the transformation (i.e., minX, minY) to the origin point is obtained.
T
=
[
1
0
-
min
X
0
1
-
min
Y
0
0
1
]
Equation
9
Upon combining the transformation matrices, i.e., upon combining the rotation matrix R and the translational transformation matrix T in this order, a matrix H p2en for transformation from a print region image coordinate system (p) to an editing image coordinate system (en) for the print medium 200 of No. n is obtained. Note that each print medium 200 is numbered in accordance with its location.
H p2en =T·R
Upon transformation of the image coordinate system of the print surface 200 a such as one illustrated in FIG. 9A by the transformation matrix H p2en , the print surface 200 a is changed to the given orientation 200 b as illustrated in FIG. 9C . In other words, the print surface 200 a is normalized. Accordingly, image data of the normalized print surface 200 a is acquired.
Upon normalization of the print surface 200 a , the worker edits, on the normalized print surface 200 a , print data to be printed on the print surface 200 a in Step S 320 . Specifically, when editing print data by utilizing editing software capable of editing print data, the worker edits the print data on the image data of the changed print surface 200 b . Thus, as illustrated in FIG. 10A , the worker decides where to perform printing on the print surface 200 a , and what kind of design to print. Examples of the design to be printed include a graphic form, a character and a picture.
Upon completion of editing of the print data by the worker, the converter 56 converts the edited print data into print data printable on the pre-normalization print surface 200 a in Step S 322 . Specifically, using an inverse transformation matrix for the transformation matrix H p2en calculated before the normalization of the print surface 200 a , the print data edited by the worker in Step S 320 is transformed, and the transformed print data is stored as print data to be used in actual printing (see FIGS. 10B and 10C ).
After the print data has been generated in Step S 322 , the worker provides an instruction to start printing and then the microcomputer 300 controls the printer 10 so as to perform printing based on the generated print data in Step S 324 .
As described above, in the printer 10 according to the present preferred embodiment, images are taken while an 8-bit Gray code pattern is projected on the base sheet 30 with no print medium 200 placed on the base sheet 30 , and vertical and horizontal spatial code images are acquired by the spatial code image generator 50 based on the taken images. Furthermore, images are taken while an 8-bit Gray code pattern is projected on the print media 200 with the print media 200 placed on the base sheet 30 , and vertical and horizontal spatial code images are acquired by the spatial code image generator 50 based on the taken images.
Note that the position of the upper surface 30 a of the base sheet 30 when no print medium 200 is placed on the base sheet 30 and the position of the print surface 200 a of the print medium 200 when the print medium 200 is placed on the base sheet 30 coincide with the position of the upper surface 14 a of the table 14 in the Z-axis direction (vertical direction) which is located at the time of the calibration.
Then, the image generator 52 obtains a difference between the vertical and horizontal spatial code images with no print medium 200 and the vertical and horizontal spatial code images with the print media 200 , thus acquiring an image of the print surface 200 a of each print medium 200 .
Subsequently, the normalizer 54 sets a quadrilateral to an outline of each print surface 200 a in the image of the print surface 200 a of each print medium 200 and calculates the orientation and origin point of each print surface 200 a so as to normalize each print surface 200 a.
When print data to be printed on each print surface 200 a has been edited by the worker on the normalized print surface 200 a , the converter 56 converts the print data, edited by the worker, into print data printable on the pre-normalization print surface 200 a , and stores this print data.
Then, using the converted print data, printing is performed on the print surface 200 a of each print medium 200 .
Although the worker has to perform an operation such as lowering of the table 14 , the printer 10 according to the present preferred embodiment does not require an exacting operation such as accurate positioning. Consequently, unlike a conventional printer, the printer 10 according to the present preferred embodiment is capable of performing printing on the three-dimensional print medium 200 by simple operations.
The printer 10 according to the present preferred embodiment is capable of performing printing on the three-dimensional print medium 200 without using a jig.
Even when the print media 200 are produced in low quantities, the printer 10 according to the present preferred embodiment is capable of performing printing on the print media 200 without incurring an increase in cost.
Although one preferred embodiment of the present invention has been described thus far, the present invention is not limited to the above-described preferred embodiment but may be embodied in various other forms. Alternative exemplary preferred embodiments of the present invention will be described below.
Although the printer 10 has been described as preferably an inkjet printer in the foregoing preferred embodiment, the printer according to the present invention is not limited to an inkjet printer. Various printers such as a dot-impact printer and a laser printer, for example, may be used as the printer 10 .
Although the print medium 200 is preferably placed over the table 14 with the base sheet 30 interposed therebetween in the foregoing preferred embodiment, the print medium 200 does not necessarily have to be placed in this manner. Alternatively, the print medium 200 may be directly placed on the table 14 without the base sheet 30 interposed therebetween. In that case, the print medium 200 and/or the upper surface 14 a of the table 14 may be processed so that the print medium 200 is less prone to slip along the upper surface 14 a of the table 14 .
Although the six print media 200 are preferably placed on the base sheet 30 and printing is performed on the print surface 200 a of each print medium 200 in the foregoing preferred embodiment, the number of the print media 200 to be placed is not limited to six. For example, the number of the print media 200 to be placed on the base sheet 30 may be one, two, three, four, five, or seven or more. The regions arranged in the predetermined pattern may alternatively be arranged in a different pattern so that printing is performed on larger print media or smaller print media.
In the foregoing preferred embodiment, the print head 20 is preferably moved in the X-axis direction (right-left direction) along the rod-shaped member 16 and moved in the Y-axis direction (front-rear direction) together with the movable member 18 , and the table 14 is moved in the Z-axis direction (vertical direction), but movements of the print head 20 and the table 14 are not limited to these movements. For example, as illustrated in FIG. 11 , the printer may be arranged so that the table 14 movable up and down in the Z-axis direction is moved in the Y-axis direction, and the print head 20 is moved in the X-axis direction.
In a printer 60 illustrated in FIG. 11 , the table 14 preferably is movable along guide rails 62 provided on the base member 12 . The guide rails 62 preferably include a pair of guide rails 62 - 1 and 62 - 2 which extend in the Y-axis direction (front-rear direction) on the base member 12 . Note that the table 14 is provided with a driving mechanism (not illustrated) controlled by the microcomputer 300 so that the table 14 is moved in the Y-axis direction along the guide rails 62 . Thus, the table 14 movable in the Z-axis direction is also movable in the Y-axis direction on the base member 12 .
The print head 20 preferably is movably provided at a fixed member 66 provided on the base member 12 . More specifically, the print head 20 preferably is provided at a rod-shaped member 64 so as to be movable along the X-axis direction (right-left direction). Thus, the print head 20 preferably is moved in the X-axis direction along the fixed member 66 . The fixed member 66 preferably includes: vertical members 68 - 1 and 68 - 2 provided on the base member 12 ; and the rod-shaped member 64 through which the vertical members 68 - 1 and 68 - 2 are connected to each other. The rod-shaped member 64 extends in the X-axis direction.
The foregoing preferred embodiment and the alternative preferred embodiments described above may be combined as appropriate.
The terms and expressions used herein are provided for explanation purposes and should not be construed as being restrictive. It should be appreciated that the terms and expressions used herein do not eliminate any equivalents of features illustrated and mentioned herein, but allow various modifications falling within the claimed scope of the present invention. The present invention may be embodied in many different forms. The present disclosure is to be considered as providing examples of the principles of the present invention. These examples are described herein with the understanding that such examples are not intended to limit the present invention to preferred embodiments described herein and/or illustrated herein. Hence, the present invention is not limited to the preferred embodiments described herein. The present invention includes any and all preferred embodiments including equivalent elements, modifications, omissions, combinations, adaptations and/or alterations as would be appreciated by those skilled in the art based on the present disclosure. The limitations in the claims are to be interpreted broadly based on the language included in the claims and not limited to examples described in the present specification or during the prosecution of the application.
Preferred embodiments and alternatives and modifications of preferred embodiments of the present invention are suitable for use in a printer for performing desired printing on a print medium having a flat print surface.
While preferred embodiments of the present invention have been described above, it is to be understood that variations and modifications will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. The scope of the present invention, therefore, is to be determined solely by the following claims.
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A flatbed type printer includes a table on or over which a print medium including a flat print surface is placed, a print head, a projecting unit configured to project a Gray code pattern on the table, an image taking unit configured to take an image of the projected Gray code pattern, a generating unit configured to generate a first spatial code image using an image taken with no print medium placed and to generate a second spatial code image using an image taken with the print medium placed, a generating unit configured to generate an image of the print surface using the first and second spatial code images, a normalizing unit configured to normalize the print surface in the image of the print surface, and a converting unit configured to convert print data edited on the normalized print surface into data printable on the pre-normalization print surface.
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BACKGROUND OF THE INVENTION
The present invention relates generally, as indicated, to automatic analyzing systems and, more particularly, to automatic analyzing systems for electroplating baths. Moreover, the invention relates to a method for automatic analysis, particularly of electroplating baths, and to a method and apparatus for automatic analysis and control of baths, such as electroplating baths.
In an electroplating bath or process changes ordinarily occur, for example, in the chemical balance of the bath, as electrochemical reactions occur. To help maintain the quality of the electroplated product and the efficiency of an electroplating bath, it is necessary to analyze the bath for one or more parameters. Shut down of a process or correction of the chemical composition of the bath may be based on the information obtained by such analysis.
One prior analysis technique for electroplating baths employed a Waters Associates Liquid Chromatograph into which a small quantity of liquid specimen manually taken from a bath on a daily basis was manually injected. For accuracy, though, it is desirable that the time lag between drawing a specimen and analysis thereof be minimized; however, using the manual specimen drawing and injecting technique, it is difficult both to minimize that time lag and to hold the same constant for each analysis. Moreover, the manual drawing and injecting of specimens is time consuming and expensive, especially when multiple baths must be separately analyzed on a daily basis. Although carousel-type specimen holders and delivering equipment have been available to provide multiple specimens sequentially to optical analyzing equipment, such as the mentioned liquid chromatograph, the individual specimens still must be manually drawn from respective baths and placed in the carousel which is then operated to provide semi-automatic delivery to the analyzing machine. Another disadvantage with the prior analyzing technique is the limited ability of the analyzing machine; for example, certain components of an electroplating bath may not affect the ultraviolet light of such liquid chromatograph and, thus, may defy detection or analysis thereby.
Historically the analysis of electroplating solutions has met with difficulty. Combinations of traditional chemical analysis, e.g. Peter Wolfram Wild Modern Analysis For Electroplating, (Finishing Publications Limited, Middlesex, U.K., 1974), and qualitative performance analysis, such as the Hull Cell, e.g. U.S. Pat. No. 2,149,344, have had to suffice. One recent innovation has been the use of cyclic stripping voltometry, e.g. U.S. Pat. No. 4,132,605 to characterize quantitatively the performance of a copper electroplating bath. Despite these methods of control and analysis it often occurs that poor plating characteristics manifest themselves over time as the solutions are used. Organic contaminants, trace metals, and oxidation or reduction products from the electrolysis of "brightening" or leveling addition agents may accumulate so as to eventually deleteriously affect performance of the electroplating solution.
In the past the use of chromatographic separation techniques that are reproducible provided proper detection is also employed may show buildup of materials not deliberately added to the electroplating solution. If correlative changes in the concentration of these non-deliberately added compounds with the change in plating performance are noted, the electroplater may be able to anticipate changes in performance before they adversely affect the quality of his work.
To provide frequent analysis, so that meaningful data may be accrued, is a primary intent of this invention.
SUMMARY OF THE INVENTION
Briefly, the invention provides an improved method and apparatus for analyzing the concentrations of chemical components in a bath, especially in an electroplating bath, contained in a processing tank. Moreover, the information obtained by such analysis of a single bath or of multiple baths may be efficiently employed to control such concentrations in the bath or respective baths, for example, by controlling the addition of one or more additives. Of course, other types of control also may be effected, such as, for example, temperature control and the like.
Thus, principal objects of the invention are to improve the accuracy and completeness and to facilitate the making of chemical analyses, especially of electroplating baths.
Other objects are to improve the accuracy, completeness and facility of control of concentrations of components and/or other properties of baths, especially of electroplating baths.
Additional objects are to improve the precision of electroplating baths and of the electroplating effected thereby.
Further objects are to provide programmability for analysis of electroplating baths, including the frequency with which such analyses are made, the duration of respective analyses, the nature of respective analyses (for example, the equipment used and/or the parameters used in equipment for making analyses), the number of baths analyzed, etc.
Still other objects are to obtain one or more of the foregoing and further objects and advantages while providing for analysis and/or control of multiple baths, especially of electroplating baths.
Still an additional object is to enable the facile and convenient use of high pressure liquid chromatography for monitoring and/or analyzing processes using continuous relatively low pressure on-stream sampling.
The foregoing and other objects and advantages of the present invention are obtained in an analyzer for liquid solutions, mixtures, and the like, and preferably for electroplating baths, comprising a supply means for supplying a sample for analysis and a detector means for detecting the concentration of at least one component in the sample. Preferably the supply means supplies a stream of liquid from an electroplating bath, and a selecting means selects a sample of this stream of liquid for analysis. Moreover, preferably the detector means includes plural detectors for detecting several components of the sample. Further, a pressurizing means may be provided for receiving a sample at relatively low pressure and for delivering such sample at relatively high pressure to the detector means for relatively high pressure analysis thereby. Also, the invention may include a controlled solvent delivery means for delivering at least two solvents selectively to transport a sample to and through the detector means. Preferably one or more portions of the analyzer is computer controlled, for example by a microprocessor type microcomputer, for accuracy, repeatability, and reliability of the analysis information. Furthermore, the analysis information may be employed in the invention to control the delivery of additives or to control another parameter of the analyzed bath or process to maintain the composition or another parameter of the same within predetermined tolerances.
These and other objects and advantages in accordance with the preferred embodiment and best mode of the present invention, moreover, are obtained by continuous on-stream sampling of one or more electroplating baths and selected analyzing of the same with the versatility of a combined detector system, especially for electroplating baths. Preferably such combination detector system employs both an electrochemical detector, such as a polarograph type device and a spectrophotometric type device, with the latter being upstream of the form so as not to affect the aliquot analyzed thereby and, therefore, the nature of the output information derived by the former.
To the accomplishment of the foregoing and related ends, the invention, then, comprises the features hereinafter fully described in the specification and particularly pointed out in the claims, the following description and the annexed drawings setting forth in detail a certain illustrative embodiment of the invention, this being indicative, however, of but one of the various ways in which the principles of the invention may be employed.
BRIEF DESCRIPTION OF THE DRAWINGS
In the annexed drawings:
FIG. 1 is a block diagram of an analyzer for liquid solutions, and particularly for electroplating baths, in accordance with the present invention;
FIG. 2 is a schematic fluid and electrical diagram, partly in block form, of the analyzer of FIG. 1; and
FIG. 3 is a fragmentary schematic illustration of portions of the multiple sampling and high pressure sample introduction system of the analyzer.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The analyzer of the present invention is described herein in connection with one for analyzing the concentration of components in an electroplating bath or process (used interchangeably below). However, it will be appreciated that the invention may be used to analyze other liquids. In accordance with the preferred embodiment and best mode of the invention, several electroplating baths are continuously sampled and periodically automatically analyzed; however, it will be appreciated that the invention may be used for analysis of only one bath.
Referring now in detail to the drawings, wherein like reference numerals designate like parts in the several figures, and initially to FIG. 1, an analyzer for continuously sampling and periodically automatically analyzing plural electroplating baths is generally indicated at 1. The analyzer 1 includes a high pressure solvent delivery system 2, a multiple sampling and high pressure sample introduction system 3, both of which preferably are computer controlled, for example by a microprocessor controller 4, a detector system 5, and an information output device 6. Preferably the detector system 5 includes plural detector stages 7, 8 so that in the event that one detector stage is incapable of detecting a particular component of a sample, the other detector stage may be able to detect that component. In the preferred embodiment and best mode, prior to or upstream of the first detector stage 7 is a high pressure liquid chromatography (HPLC) column 10 and such first stage includes a spectrophotometric type detector, most preferably an ultraviolet electromagnetic radiation detector 11; and the second detector stage 8 is an electro-chemical detector 12, such as a commercially available polarograph type instrument which ordinarily is equipped with a flow cell. The information output device 6 preferably includes a multi-channel strip chart recorder 13 which displays output information from the respective detectors 11, 12 integrated with respect to time, as the chart paper is moved through the recorder; and a data acquisition and utilization device 14, which may include an electronic data manipulation and/or storage mechanism for storing information from the detectors as well as a further control mechanism for controlling a parameter of respective analyzed baths. For example, the data acquisition and utilization device 14 may include a minicomputer which controls one or more valves that provide additives to a bath to maintain the chemical nature of the latter within predetermined tolerances; the device 14 may control other parameters of the bath, such as temperature thereof, or may control external equipment, such as a shut-down mechanism or feed equipment that feed product into the bath for electroplating purposes based on the analysis information obtained by the analyzer 1.
Turning particularly to FIG. 2, the analyzer 1 is illustrated in greater detail. In achieving the objective of the analyzer 1, namely the analysis of respective liquid samples from electroplating baths, the individual samples are obtained at relatively low pressure and are combined with and pumped with one or more solvents at relatively high pressure through the HPLC column 10 to the first detector stage 7. The actual solvent material that flows through the detector system 5 will be referred to hereafter as the mobile phase. An aliquot of sample from a process bath mixed with and pumped with solvent, for example, is affected by the packing of the HPLC column 10 and is examined by the respective ultraviolet and polarographic type detectors 11, 12. The high pressure at which the solvents and the aliquot are pumped is necessary due to the resistance to flow of the HPLC column 10. The analyzer 1 is versatile in several respects, including the ability to analyze samples from plural electroplating baths, to effect such analysis using plural detectors which use different detection techniques, and to use one or more solvents individually with a sample to make an aliquot or mobile phase and/or to use various combinations of solvents at adjustably controlled percentages for the same.
To monitor periodically and automatically several processes, i.e. several electroplating baths, which are not at exceptionally low pressures or at high or low temperatures and which are occurring in solution, plural flow streams of liquid are taken, one from each monitored bath, and a single sample selection valve 20 that is controlled by the microprocessor 4 is employed to switch process streams, i.e. selectively to deliver a respective stream for analysis. The valve 20 preferably operates or switches in response to pneumatic signals on pneumatic lines 21, 22, which are coupled to the microprocessor controller 4. Thus, the microprocessor controller 4 may be, for example, an Altex Model 420 Microprocessor Control, which includes a microprocessor integrated circuit and associated support circuitry, memory circuitry, etc. and pneumatic input and output lines controlled thereby. Such pneumatic operation of the valve 20 provides reliable control thereof. Directly associated with the valve 20 is a peristaltic pump 23, such as a Buchler multiple vane, e.g. a 4-vane, 8-vane, or the like, multistatic pump. Moreover, the valve 20 preferably is a Valco Model AHCSF 4-HPA (the digit 4 represents the number of streams and in the preferred embodiment and best mode would be a digit 8 to indicate 8 streams) Stream Valve of Hastalloy C material together with a multiple way, 4-way, 8-way, etc., depending on the number of streams, air switch for operating the valve in response to the pneumatic signals on lines 21, 22 from the microprocessor controller 4.
Referring briefly to FIG. 3, the sample selection valve 20 and the peristaltic pump 23 are schematically illustrated. For convenience of illustration the valve 20 in FIG. 3 has only six flow channels, such as the channel 24, which has an inlet flow path 25, an outlet flow path 26, and a flow path completing mechanism or valving mechanism 27. The valving mechanism 27 may be operated selectively in response to pneumatic signals from the microprocessor controller 4 to complete or to interrupt the fluid connection between paths 25, 26 and in the latter condition importantly to connect the inlet flow path 25 with a common flow channel 28. Such a connection is illustrated in the sampling channel 29 in which the outlet flow path 30 is disconnected from the inlet flow path 31 and the latter is connected by the valving mechanism 32 to the common flow channel 28. All of the valving mechanisms, such as 27, 32, may be considered a flow selector of the valve 20. Preferably each of the respective inlet flow paths, such as 25, 31, is connected directly to a respective electroplating bath, the liquid of which is to be automatically analyzed periodically or to a reference source of liquid having concentrations of components, e.g. nickel, tin, copper, and associated organic and inorganic addition agents, against which those of the baths are to be compared; additionally, each outlet flow path, such as 26, 30, is connected directly back to the bath or source to which the associated inlet flow path, such as 25, 31, is connected. The pump 23 may include, for example, a constant speed electric motor 33 with an output shaft 34 on which are mounted plural pumping peristaltic cams, such as at 35, 36, for common rotation by the shaft 34 to pump fluid in the respective channels, suh as 24, 29. Accordingly, the inlet flow path, such as 25, 31, of each channel may include a flexible portion that is cooperative with a respective cam, such as 35, 36, to provide peristaltic pumping action in the respective channels. In FIG. 2 lines 31a represent other inlet flow paths from other baths, not shown, coupled to the respective pump cams and via lines 31a' to the valve 20; and lines 30a represent other respective outlet flow paths of respective flow channels for returning respective streams to their sources.
Thus, when a respective valving mechanism, such as 27, is closed to complete a flow path between the inlet and outlet flow paths 25, 26 of a given channel, liquid from the electroplating bath into which the flow path 25 extends is pumped through the channel and back via the outlet flow path 26 into the same electroplating bath to provide a continuous flow stream accurately representative of the present conditions, including, particularly, the chemical concentrations, of the respective electroplating bath. However, when a respective valving mechanism or flow selector, such as at 32, is operated in the valve 20 to disrupt the connection with the outlet flow path 30 and to connect the inlet flow path 31 with the common flow channel 28, liquid from the electroplating bath flowing in the channel 29 is obtained and directed through an outlet channel 40 of the valve 20 for subsequent analysis. Accordingly, not only are the flow streams continuously flowing in the respective baths, but also the sample that is to be analyzed by the analyzer 1 is an on-stream sample which accurately represents the present conditions in the bath which will be analyzed as will be described in further detail below.
Turning back to FIG. 2, fluid intake and output fitting 41, 42 associated with the inlet and outlet flow paths 31, 30 for drawing liquid from and returning liquid to an electroplating bath 43 are illustrated. For convenience of illustration the additional flow channels of the valve 20 are not seen in FIG. 2. There are, of course, several advantages to using the described peristaltic pump 23. For example, plural streams may be pumped independently of each other in a convenient manner. Moreover, the interruption of a supply of liquid to the inlet fitting 41 or a blockage of a portion of the flow path downstream of the peristaltic cam, such as 36, will not adversely affect the pump or cause too high pressure in a flow line, and, therefore, ordinarily would not require a shut-down of the analyzer 1 while the pump 23 continues to pump liquid in the flow streams of the other channels of the valve 20. Moreover, the action of the peristaltic pump 23 preferably is relatively gradual so that the liquid flowing in the respective channels is not moving at high velocity nor is any undesirable turbulence created in the bath 43 by the small amount of liquid flowing through the respective flow channel associated therewith. Alternatively, other pumps may be used.
Use of such a described sample selection valve 20 minimizes the time lag between that at which a sample is drawn from a bath 43 and that at which analysis of the sample is made. When a particular process or bath is not being analyzed, the valve 20 is appropriately actuated so that the sample stream therefrom is returned to the process tank; whereas, when a process is to be analyzed, the valve 20 is properly actuated by the microprocessor controller 4 to direct the sample stream to a high pressure sample injection valve 50. Moreover, it will be appreciated that the valve 20 may be manufactured at relatively minimum cost since the liquids flowing therein are at relatively low pressure, with high pressure liquids being limited only to the sample injection valve 50 and those portions of the analyzer fluidically downstream of such valve.
The high pressure sample injection valve 50 may be a Rheodyne Model 7120 Syringe Loading Sample Injector which is modified to operate as a loop injector; such loop 51 has a fixed volume, for example on the order of one or several microliters, to obtain a known volume of liquid sample for analysis. The sample injection valve 50 is positioned between the sample selection valve 20 and the high pressure liquid chromatographic column 10. It is the purpose of the injection valve 50 both to obtain a known quantity of relatively uncontaminated liquid for analysis and to combine such quantity of liquid with a solvent liquid received from a solvent input line 52 for subsequent high pressure analysis.
The sample injection valve 50 is schematically illustrated in FIG. 3 including a valve housing 53 with a first group of flow paths 54A, B, C and a second group of flow paths 55A, B, C as well as a series of fluid ports 61-66. The sample injection valve 50 has two operational modes or positions directly controlled by pneumatic signals on lines 67, 68 from the microprocessor controller 4. In the load position, the first group of flow paths 54A, B, C conduct fluid. Thus, the mobile phase is simply the solvent received in the solvent input line 52, and that mobile phase flows through the port 62, flow path 54A, port 63, and analysis flow line 70 continuously to the HPLC column 10; and simultaneously the flow stream from channel 29 flows through the sample selection valve 20 through the outlet channel 40 to port 66 and from the latter via flow path 54C, port 61, loop 51, port 64, flow path 54B, port 65, and waste line 71 to a waste container 72. Thus, the sample loop 51 is continuously being filled with representative samples from the process tank electroplating bath 43.
In the second or sample inject position of the sample injection valve 50, fluid connections are effected only through the second group of flow paths 55A, B, C. In this position the flow of mobile phase solvent from solvent input line 52 and port 62 is directed through flow path 55A and port 61 through the loop 51 which contains the representative sample for analysis to form an aliquot therewith. The aliquot then flows to the HPLC column 10 (FIG. 2). In this manner a representative sample from the process tank 43 is volumetrically applied to the HPLC column 10.
With accurate control of the sample injection valve 50 by the microprocessor controller 4, and coordinated activity by the latter of the sample selection valve 20, so that the stream flowing through the outlet channel 40 is switched in time for the loop 51 to be loaded with a representative process tank sample before injection and then injected, say every hour, a process may be periodically monitored automatically and substantially continuously, i.e. every hour as opposed to once per day.
The high pressure solvent delivery system 2 has available two sources 80, 81 of solvents A, B, one of which may be water, that may be individually delivered to the solvent input line 52 or may be mixed in predetermined proportions prior to delivery to the line 52. The convenient availability of plural solvents, in this case two, but it will be appreciated that more than two may be used, if desired, further increases the over-all versatility of the analyzer 1. In the solvent delivery system 2 a source 82 of inert gas, such as helium, pressurizes the solvent sources 80, 81 to purge or degas the solvents of oxygen prior to delivery by tubes 83, 84 to individual high pressure pumps 85, 86. The pumps 85, 86 may be Altex Model 110 Solvent Metering Pumps, which are electronically controlled by signals on lines 87, 88 from the microprocessor controller 4, that produce an output flow in output lines 89, 90 at from about one to about five ml. per minute, preferably at about 2 ml. per minute, and at a pressure of from about 1000 to about 10,000 psi, usually about 2000 psi, generally in dependence on the characteristics of the column 10 and solvent flow rate, delivered to a mixing chamber 91, which may be a conventional high pressure solvent mixing chamber manufactured by Altex. Thus, depending on the electrical signals on lines 87, 88 from the microprocessor 4, the amount of solvent liquids pumped by the pumps 85, 86 will be controlled so that the solvent in solvent input line 52 for delivery to the sample injection valve 50 may be either solvent individually or a mixture of the solvents in proportions controlled by the microprocessor controller.
The microprocessor controller 4 accordingly provides a plurality of functions, as aforesaid, as well as additional functions to be described below in connection with the detector system 5 and information output device 6. Thus, the microprocessor controller 4 must be able to keep track of time with good precision; it should be able to control the high pressure pumps 85, 86 so that they provide a constant flow; it should be able to control the mobile phase solvent mixtures; it should actuate the sample selection valve 20 at specified time intervals, for example by controlling delivery of a pneumatic fluid such as inert nitrogen 92, through the pneumatic lines 21, 22; it must actuate the high pressure sample injection valve 50 by controlling the supply of pneumatic fluid to lines 67, 68 at specified time intervals; and, optionally, it can turn on and off a variety of devices, including, for example, the high pressure pumps 85, 86, the peristaltic pump 33, the detectors in the detector system 5, and the recorder 13, and it may signal the beginning of an event, such as sample injection, for the recorder 13, for another recorder in the data acquisition and utilization device 14, another microprocessor or computer associated with the device 14, etc.
In the detector system 5 there are plural detector stages, in the preferred embodiment two detector stages 7, 8. Preferably the detector stages are selected to complement each other so that those components of an electroplating bath which ordinarily may not be detected by one of the detector stages may be detected by the other one. Moreover, by placing the detector stages in fluid serial flow through relation and using at the input to the upstream detector a separation mechanism, such as a HPLC column 10, that affects or separates the sample flowing therethrough, such affectation may be utilized to facilitate analysis of samples by both detectors.
In the preferred embodiment and best mode of the invention the detector stage 7 is a spectrophotometric detector or other optical type detector or like detector that will not affect the aliquot, and most preferably is an ultraviolet electromagnetic radiation detector 11. The detector stage 8 is an electrochemical detector 12 which uses a polarography, differential polarography, or normal pulse polarography type analytical technique depending on electrical voltage signals delivered thereto by a potentiostat 93, as controlled by the microprocessor controller 4.
The characteristics of an HPLC column 10 are well known, for example, as described in Liquid Chromatography in Practice, P.A. Bristow (H. Oldfield & Son, Ltd., Macclesfield, United Kingdom, 1976). In the present invention, the HPLC column 10 must have a solid phase or liquid-solid phase, as is well known, which competes for the "affinity" of sample molecules in the mobile phase. The competition for this "affinity" between solid and mobile phases causes sample molecules to be delayed in their elution from the downstream end of the column and thus separation occurs. For the most part, a solid phase of bonded octyldecyl silane is sufficient in the chromatographic separations. The mobile phase may vary in concentration of two or more components from sample type to sample type. Therefore, if desired, the HPLC column 10 may actually comprise several parallel columns with a high pressure column switching valve between the sample injection valve 50 and the respective columns to select the individual column through which respective samples may flow; each column, of course, would have a different packing material. However, it is delivered that even though a process may vary greatly in application, for example gold electroplating and nickel electroplating, the similarities in the process, such as water solubility, make column selection less critical than proper mobile phase selection. Therefore, the high pressure solvent delivery system 2 may be accurately controlled to assure consistent, yet selectively changeable, mobile phase compositions so that switching of HPLC columns ordinarily will be unnecessary.
A wide variety of ultraviolet electromagnetic radiation detectors has been used in connection with liquid chromatography, as is described, for example, in the Bristow text. If a solvent is used that absorbs little or no ultraviolet radiation at a specified wavelength, say between 190 nm. and 350 nm., and a component of a process does absorb radiation at that wavelength, the difference in absorption is proportional to the concentration of the component. The magnitudes of such absorptions can be detected in conventional manner by the detector 11 and signals representative of absorption can be delivered on lines 94 to the recorder 13. By integrating the absorption information versus the flow of the mobile phase, an accurate concentration of the component relative to other components or relative to a standard may be obtained. The recorder 13, which preferably is a strip chart recorder, facilitates such integration by recording absorbance continuously while the chart paper moves at a fixed rate, which is in effect directly proportional to the flow rate of the mobile phase through the column 10 and detector 11. Therefore, as a component passes through the detector 11 a peak of absorbance versus time or volume, as flow rate, if constant, is proportional to time, is recorded. The area under the peak, then, is proportional to concentration of that component. If desired, of course, other types of recorders and/or integrators may be used.
Although all components of a process may not absorb ultraviolet radiation, a large variety of organic molecules, all metallic ions, and most anions may affect the current being evolved between two electrodes kept at a known potential or pulsed at regular voltage steps. The electrochemical detector 12, which may be one sold by Princeton Applied Research, Model 303, Dropping Mercury Electrode System with a flow cell adapter in combination with the potentiostat voltage supply source 93, such as a Princeton Applied Research Model 364 polarographic analyzer, which delivers a controlled voltage to the electrodes of the detector 12. If a mobile phase solvent is being passed between the electrodes of the detector 12, which are located in a conventional flow cell, a constant amperage due to reduction or oxidation of the solvent at the working electrode, which is preferably a glassy carbon electrode (G.C.E.) or a dropping mercury electrode (D.M.E.), is present. This amperage is subject to radical changes if a component passes the working electrode that is oxidized or reduced. The change in current at the working electrode is, as in the case of the ultraviolet radiation absorption, proportional to the concentration of the component being oxidized or reduced, although such a proportional relation may not necessarily be a linear one. In electroplating solutions, all metal ions that can be reduced and all active brightener components affect reduction at the cathode. Therefore, the electrochemical detector 12 is particularly useful for analysis and/or control of electroplating solutions. The output information from the electrochemical detector 12 may be delivered via line 95 to the recorder 13 for handling, i.e. recording and effective integration, essentially in the same manner that the data from the ultraviolet detector 11 is handled by the recorder 13.
During analysis of the mobile phase flowing through the detector system 5, then, such mobile phase flows through the HPLC column 10, flow line 96, ultraviolet detector 11, flow line 97, the flow cell of the electrochemical detector 12, and flow line 98 to a waste receptacle 99. A source of inert gas 100, such as nitrogen, may be connected to the electrochemical detector 12 for normal purposes, such as purging, reference signal generation, etc. Moreover, the microprocessor controller 4 may provide control signals via line 100 to control the wavelength at which the ultraviolet radiation detector 11 operates to provide further versatility for the analyzer 1. Additionally, the microprocessor controller 4 may provide electrical control signals on line 101 to cause the potentiostat 93 to vary the voltage delivered and fed back on lines 102 with respect to the electrochemical detector 12 during operation of the latter to utilize the various analytical techniques of, for example, polarography, differential polarography, or normal pulse polarography. Further, it will be appreciated that varying the operational wavelength of the ultraviolet detector 11 and/or the voltage at which the electrochemical detector 12 operates during an analytical run may help to detect the concentration of components that could not be analyzed at other wavelengths or voltages; however, in the preferred embodiment and best mode, ordinarily such variations would not be used.
Data acquisition from the detector system 5 may be effected by means other than a strip chart recorder 13. In particular, the data acquisition and utilization device 14 may be coupled by lines 110, 111 to receive electrical signals from the ultraviolet and electrochemical detectors 11, 12 and may include, for example, a computer that can integrate the peak area electronically and recognize individual peaks by their elution volume. Such computer may comprise part of the microprocessor controller 4 or may be a separate computer, such as a minicomputer 112, which may be a Hewlett-Packard Model 9125 minicomputer. Such computer 112 may also be programmed to activate pumps, not shown, valves, such as valve 113, to add chemical additives, say from a storage tank 114, to the process tank based on the analysis made by the analyzer 1 of that particular process tank, e.g. process tank or bath 43, etc. Preferably the valve 113 is an electrically responsive one that will fail only in a closed position and requires an affirmative signal to open. The computer 112 may have several output lines 115, 116, 117, etc. for controlling respective chemical additives for a single bath, for plural baths, etc. Moreover, a tie-in bus 118 provides interconnection between the microprocessor controller 4 and the computer 112 for coordinated operation thereof. It will be appreciated that a single computer, such as a minicomputer or a microprocessor controller having adequate capacity, may be substituted for the microprocessor 4 and computer 112 to effect the functional operations thereof.
It also will be appreciated that the computer 112 may effect other control functions with respect to the process bath 43, such as, for example, controlling temperature thereof, the speed with which product is passed therethrough, the amount of product passed therethrough for electroplating purposes, shut-down of an electroplating process, as well as the addition of chemicals thereto.
Exemplary operation of an analyzer in accordance with the present invention is presented in two examples below.
EXAMPLE 1
A liquid for an electroplating bath is analyzed. A 20 minute automatically repeatable cycle of operation of the analyzer 1 is programmed into the microprocessor 4 via the keyboard 120 associated therewith. For the initial condition, i.e. prior to time zero, a continuous stream of electroplating solution is being pumped via line 31 and pump 23 to the sample injection valve 50, through the sample loop 51 and back to the plating solution so that the sample loop is filled with refreshed representative solution ready for analysis. At time zero, i.e. at the start of the cycle, a mixture of solvents from sources 80, 81 is pumped by pumps 85, 86 and mixed in mixing chamber 91 for delivery via the solvent input line 52 to the sample injection valve 50; also at time zero the sample injection valve 50 is operated to the inject position so that such solvent mixture is pumped through the sample loop 51 to mix with the sample therein and to pump the same through the detector system 5 for analysis thereby, as aforesaid. At one minute into the cycle the sample injection valve 50 is switched to the load position so that shortly thereafter only the solvent mixture continues to pass through the detector system 5. At fifteen minutes into the cycle the proportions of solvents delivered to the sample injection valve 50 commences to change gradually over a following two minute time period so that the solvent mixture delivered to the sample injection valve thereafter is exclusively the solvent B contained in source 81. At nineteen minutes into the cycle an alarm, not shown, is energized to indicate that the end of that cycle and, more importantly, the beginning of the next cycle, is approaching in one minute. At twenty minutes into the cycle, the program returns to time zero, whereupon the program repeats effectively to obtain injection of a sample into the mobile phase analyzed by the detector system 5.
Moreover, preferably at the beginning of each cycle, i.e. at time zero, the proportions of the two solvents delivered to and mixed in the mixing chamber changes gradually so that for the first ten minutes of the cycle the mixture in line 52 will gradually change from 100% of solvent B to equal proportions of solvents A and B. During the entire analysis process the detector system 5 provides output information particularly at the recorder 13 which provides graphical output information indicative of the concentrations of the materials flowing through the detector system 5.
EXAMPLE 2
The ultraviolet detector 11, electrochemical detector 12, peristaltic pump 33 and microprocessor controller 4 are all on. Representative streams (lag time less than two minutes) are being pumped continuously through a 16-port (8 sample stream) sample selection valve 20. The solvent A in the system is water, and the other solvent B source 81 is acetonitrile (CH 3 CN). The sample selection valve 20 is directing sample from a water reservoir, not shown, through the sample loop 51 of injection valve 50 which is in the load position to keep the valve clean. The sequence of events occurring over a one hour (from Time 0 minutes to Time 60 minutes) is, as follows:
__________________________________________________________________________Time__________________________________________________________________________0 High pressure pumps 85, 86 are started at a combined flow = 2 milliliter/minute; the mobile phase composition in line 52 is adjusted to 20% CH.sub.3 CN (solvent A is 80% and solvent B is 20% of the combined flow); recorder 13 turned on; sample selection valve 26 is rotated to a nickle standard stream, not shown, containing nickel and nickel salts and associated organic and inorganic additives in aqueous solution at a predetermined desired concen- tration.2 Sample injection valve 50 switched to inject; signal to recorder 13 to record analyzed information (the signals to the recorder mentioned below also effect recording of information for at least the time period that valuable analysis information would be expected from the detector system).2.2 Sample injection valve 50 switched to load.2.3 Sample selection valve 20 switched to nickel plating bath stream, say from bath 43.8 All components of the nickel standard sample have been sepa- rated, analyzed and recorded; sample injection valve 50 switched to inject; signal to recorder 13.8.2 Sample injection valve 50 switched to load; sample selection valve 20 switched to water.10 Sample selection valve switched to Copper Standard.13 All components of the nickel plating bath have been separated and recorded; solvent composition changed to 50% CH.sub.3 CN (it takes 5 minutes for this to equilibrate).25 Sample injection valve switched to inject; signal to recorder 13.25.2 Sample injection valve switched to load; sample selection valve switched to copper plating bath stream.30 All copper standard components have been separated and re- corded; sample injection valve switched to inject; signal to recorder 13; sample selection valve changed to water.30.2 Sample injection valve switched to load.32 Sample selection valve changed to tin standard.35 All copper plating bath components have been analyzed and recorded; sample injection valve switched to inject; signal to recorder 13.35.2 Sample injection valve switched to load.40 All tin components have been separated and recorded; sample injection valve switched to inject; signal to recorder 13.40.2 Sample injection valve switched to load; sample selection valve switched to water.45 All tin plating bath components have been separated and recorded; mobile phase composition changed to 20% CH.sub.3 CN (this takes 5 minutes for equilibration).50 High pressure pumps off(flow = 0), recorder off.60 Start sequence again at 0.__________________________________________________________________________
In view of the foregoing it will be appreciated that the analyzer 1 may be used effectively to analyze electroplating baths and other liquids, solutions, mixtures, etc. and, if desired, to provide automatic control of the monitored process.
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The invention provides an on-stream method and apparatus for analyzing of the concentrations of chemical components in a bath, especially in an electroplating bath, contained in one or more processing tanks. Moreover, the information obtained by such analysis of a single bath or of multiple baths may be efficiently employed to control such concentrations in the bath or respective baths, for example, by controlling the addition of one or more additives. The apparatus comprises a multi-steam sampling value and a computer for controlling the operation of said value. The computer also controls means for adding material to the baths in order to maintain the parameters thereof.
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The present is a continuation-in-part of U.S. patent application Ser. No. 09/280,569 filed Mar. 30, 1999, now abandoned.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a hydroxyphenyl derivatives which have HIV integrase inhibitory properties that have been characterized by specific structural and physicochemical features. This inhibitory property may be advantageously used, for example, to provide medicinals (e.g. compositions) with antiviral properties against HIV viruses, including the HIV-1 and HIV-2 viruses, i.e. the hydroxyphenyl derivatives including pharmaceutical compositions thereof may be used to inhibit the activity of HIV integrase.
BACKGROUND OF THE INVENTION
The HIV (human immunodeficiency virus) retrovirus is the causative agent for AIDS (acquired immunodeficiency syndrome). Thus the HIV-1 retrovirus primarily uses the CD4 receptor (a 58 kDa transmembrane protein) to gain entry into cells, through high-affinity interactions between the viral envelope glycoprotein (gp 120) and a specific region of the CD4 molecule found in T-lymphocytes and CD4 (+) T-helper cells (Lasky L. A. et al., Cell vol. 50, p. 975-985 (1987)). HIV infection is characterized by a period immediately following infection called “asymptomatic” which is devoid of clinical manifestations in the patient. Progressive HIV-induced destruction of the immune system then leads to increased susceptibility to opportunistic infections, which eventually produces a syndrom called AIDS-related complex (ARC) characterized by symptoms such as persistent generalized lymphadenopathy, fever, weight loss, followed itself by full blown AIDS. After entry of the retrovirus into a cell, viral RNA is converted into DNA, which is then integrated into the host cell DNA. The reverse transcriptase encoded by the virus genome catalyzes the first of these reactions (Haseltine W. A. FASEB J. vol 5, p. 2349-2360 (1991)). At least three functions have been attributed to the reverse transcriptase: RNA-dependent DNA polymerase activity which catalyzes the synthesis of the minus strand DNA from viral RNA, ribonuclease H (RNase H) activity which cleaves the RNA template from RNA-DNA hybrids and DNA-dependent DNA polymerase activity which catalyzes the synthesis of a second DNA strand from the minus strand DNA template (Goff S. P. J. Acq. Imm. Defic. Syndr. Vol 3, p. 817-831 (1990)). The double stranded DNA produced by reverse transcriptase, now called provirus, is then able to be inserted into host genomic DNA. At the end of reverse transcription, the viral genome now in the form of DNA is integrated into host genomic DNA and serves as a template for viral gene expression by the host transcription system, which leads eventually to virus replication (Roth et al.,1989). The preintegration complex consists of integrase, reverse transcriptase, p17 and proviral DNA (Bukrinsky M. I., Proc. Natn. Acad. Sci. USA vol. 89 p.6580-6584 (1992)). The phosphorylated p17 protein plays a key role in targeting the preintegration complex into the nucleus of host cell (Gallay et al., 1995).
The primary RNA transcripts made from the provirus are synthesized by the host cell RNA polymerase II which is modulated by two virus-encoded proteins called tat and rev. The viral proteins are formed as polyproteins.
Post-translational modifications of viral polyproteins include processing and glycosylation of Env (envelope) proteins, and myristylation of the N-terminal residue of the p17 protein in the Gag and Gag-Pol polyproteins. The latter two precursors correspond to structural proteins and viral enzymes. The viral protease is involved in processing polyproteins Gag and Gag-Pol into mature proteins, a step essential for virus infectivity.
A number of synthetic antiviral agents have been designed to block various stages in the replication cycle of HIV. These agents include compounds which interfere with viral binding to CD4 T-lymphocytes (for example, soluble CD4), compounds which block viral reverse transcriptase (for example, didanosine and zidovudine (AZT)), budding of virion from the cell (interferon), or the viral protease (for example Ritonavir and Indinavir). Some of these agents proved ineffective in clinical tests. Others, targeting primarily early stages of viral replication, have no effect on the production of infectious virions in chronically infected cells. Furthermore, administration of many of these agents in effective therapeutic doses has led to cell-toxicity and unwanted side effects, such as anemia, neurotoxicity and bone marrow suppression. Anti-protease compounds in their present form are typically large and complex molecules of peptidic nature that tend to exhibit poor bioavailability and are not generally consistent with oral administration. These compounds often exhibit side effects such as nausea, diarrhea, liver abnormalities and kidney stones.
Accordingly, the need exists for compounds that can effectively inhibit the action of the third viral enzyme called integrase, for use as agents for treating HIV infections.
The terms HIV integrase and integrase as used herein are used interchangeably and refer to the integrase enzyme encoded by the human immunodeficiency virus type 1 or 2. In particular this term includes the human immunodeficiency virus type 1 integrase.
SUMMARY OF THE INVENTION
The present invention provides an hydroxyphenyl derivative selected from the group consisting of a compound of formula
and when a compound of formula I comprises a carboxylic acid group pharmaceutically acceptable salts thereof and when a compound of formula I comprises an amino group pharmaceutically acceptable ammonium salts thereof, wherein n is 1, 2 or 3, e is 1, 2 or 3, Hal represents a halogen atom (e.g. Cl, Br, F or I), p is 0, 1 or 2, r is 0, 1 or 2, X and X′ each independently represents a single bond, a saturated straight or branched hydrocarbon group of 1 to 4 carbon atoms or a straight or branched hydrocarbon group of 2 to 4 carbon atoms comprising a carbon to carbon double bond, R a represents H or —CH 3 , and R aa represents H or —CH 3 ; W, may for example, represent an amino acid residue or fragment (in particular alpha-amino acid residues) such as for example a residue based on tyrosine, DOPA, hydroxyproline, serine, threonine, histidine, valine, phenylalanine, lysine, alanine, glycine, glutamic acid, aspartic acid, arginine, asparagine, glutamine, leucine, lysine, isoleucine, proline, tryptophan, methionine, cysteine, cystine, thyroxine, meta-tyrosine, sarcosine, other alpha-methyl amino acids such as alpha-methyl DOPA, as well as other 3-substituted tyrosines, and the like.
W, for the above formula I, may, for example, be derived from natural or unnatural alpha-amino acids. The term unnatural alpha-amino acid refers to alpha-amino acids which do not occur in nature but which can be derived from naturally occurring alpha-amino acids or other chemical reagents by methods known to those skilled in the art.
W may, for example, represent a group of formula
wherein k is 0 or 1, A and A′ each independently represents a group of formula
R a represents H or —CH 3 , R b represents H or —CH 3 , R c represents H or OH, R is selected from the group consisting of H, CH 3 —, (CH 3 ) 2 CH—, (CH 3 ) 2 CHCH 2 —, CH 3 CH 2 CH(CH 3 )—, C 6 H 5 CH 2 —, CH 3 SCH 2 CH 2 —, HO 2 CCH 2 —, H 2 NC(O)CH 2 —, HO 2 CCH 2 CH 2 —, H 2 NC(O)CH 2 CH 2 —, H 2 NCH 2 CH 2 CH 2 CH 2 —, HOCH 2 —, CH 3 CH(OH)—, HSCH 2 —, HO 2 C—, benzyloxycarbonyl, benzyloxycarbonylmethyl,
wherein Hal is as defined above and f is 0, 1 or 2, g is 0, 1 or 2, and each q is independently 0 or 1.
The group of structure
may in particular for example be a fluoride substituted structure of formula
Similarly, the group of structure
may in particular for example be a fluoride substituted structure of formula
As mentioned, when a compound of formula I comprises a carboxylic acid group the polyhydroxy compounds may be any pharmaceutically acceptable salt thereof and when a compound of formula I comprises an amino group the polyhydroxy compounds may be any pharmaceutically acceptable ammonium salt thereof.
The present invention provides, where appropriate, salts (e.g. derived from appropriate bases or acids) which include but are not limited to alkali metal (e.g., sodium, potassium, cesium, etc.) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts such as acid addition salts of amines (e.g. ammonium chloride salts) as well as quaternary ammonium salts of for example N—(R″) 4 + type wherein R″ is an organic residue.
The pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of such acid salts include: acetate adipate, alginate aspartate benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylhydrogen-sulfate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycollate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthylsulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, perchlorate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate.
This invention also envisions the quaternization of any basic nitrogen containing groups of the compounds disclosed herein. The basic nitrogen can be quaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodide; and arylalkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization.
This invention also envisions the presence of an ester group(s) such as for example on the acidic end of an appropriate amino acid fragment(s), such as glutamic acid and aspartic acid as having some anti-integrase activity as such as acting as pro-drugs, i.e. capable of hydrolysis of the ester moiety to liberate in the systemic circulation the acid, also possessing anti-integrase activity. For example, the ether oxygen of an ester compound may be attached or linked to benzyl, a lower (branched or straight) alkyl (e.g. C 1 -C 6 alkyl) such as methyl, a lower cycloalkyl (e.g. C 3 -C 7 cycloalkyl) such as cyclohexyl, and the like. Alternatively, an ester(s) may be derived from a carboxylic acid(s) and one or more hydroxyl groups, such as for example an hydroxyl group on a phenyl ring. A carboxylic acid may, for example, comprise an acyl group having from 2 to 8 carbon atoms; the acyl group may for example comprise lower alkyl of 1 to 6 carbon atoms, lower cycloalkyl of from 3 to 7 carbon atoms, etc..
In addition, this invention further envisions the presence of structures having an amide functionality such as, for example, on the carboxylic end located on the side chain of such acids. These amides, such as simple primary, secondary or tertiary amides, possess activity of their own. In addition, it is possible to couple such acids with dopamine to yield compounds of interest. The amino moiety of an amide compound may for example be —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 , a pyrrolidine residue, a piperidine residue, a morpholine residue and the like
In any event, it is also to be understood that the present invention relates to any other compound having a structure such that, upon administration to a recipient, it is capable of providing (directly or indirectly) a compound of this invention or an antivirally active metabolite or residue thereof. Thus the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The present invention in particular provides a dopamine derivative selected from the group consisting of a compound of formula Ia
and when a compound of formula Ia comprises a carboxylic acid group pharmaceutically acceptable salts thereof and when a compound of formula Ia comprises an amino group pharmaceutically acceptable ammonium salts thereof, wherein n, R a and R are as defined above.
The present invention also provides a dopamine derivative selected from the group consisting of a compound of formula Ib
wherein n is as defined above (e.g. n may in particular be 1 or 2), and R d is selected from the group consisting of H and OH.
The present invention further relates to dipeptide derivatives i.e. to compounds of formula I defined above wherein k is 1. The present invention in particular provides an hydroxylphenyl derivative wherein for the compound of general formula I above, W represents a group of formula
wherein n is as defined above (e.g. n may in particular be 1 or 2), p is as defined above (p may in particular be 0), each R a is independently as defined above, each R b is independently as defined above, and each R is independently as defined above; more particularly, for example, for each R, f may be 0 or 1 and g may be 0 or 1.
The compounds of this invention contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomer, diastereomeric mixtures and individual diastereoisomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration.
The amino acid residues may, for example, in any event, be of L, D or DL form, preferably of L form; thus for example the amino acid residue (i.e. W) may be a L-α-amino residue, a D-α-amino residue, or a DL-α-amino residue.
Accordingly, the present invention further provides a dopamine derivative selected from the group consisting of a compound of formula Ic
and when a compound of formula Ic comprises a carboxylic acid group pharmaceutically acceptable salts thereof and when a compound of formula Ic comprises an amino group pharmaceutically acceptable ammonium salts thereof,
wherein n is 1, or 2, R a and R are as defined above (e.g. f and g may be 0 or 1 and the respective group Hal thereof may be fluorine (F)).
The present invention furthermore provides a dopamine derivative selected from the group consisting of a compound of formula Id
and when a compound of formula Id comprises a carboxylic acid group pharmaceutically acceptable salts thereof and when a compound of formula Id comprises an amino group pharmaceutically acceptable ammonium salts thereof, wherein n is 1, or 2, each R a is independently as defined above, and each R is independently as defined above; more particularly, for example, for each R, f may be 0 or 1 and g may be 0 or 1.
The compounds of the present invention including where applicable their pharmaceutically acceptable derivatives have an affinity for integrase, in particular, HIV integrase. Therefore, these compounds are useful as inhibitors of such integrase, i.e. they are in particular useful as HIV integrase inhibitors. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as antivirals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
According to the present invention, the compounds of this invention are capable of inhibiting HIV viral replication in human CD4+ T-cells, by inhibiting the ability of HIV integrase to integrate the double stranded DNA into host genomic DNA for further virus replication by the host cell machinery (Sakai H., J. Virol. Vol. 67 p. 1169-1174 (1993)). These novel compounds can thus serve to reduce the production of infectious virions from acutely infected cells, and can inhibit the initial or further infection of host cells. Accordingly, these compounds are useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-1 and related viruses, which may result in asymptomatic HIV-1 infection, AIDS-related complex (ARC), acquired immunodeficiency syndrome (AIDS), AIDS-related dementia, or similar diseases of the immune system.
Thus the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of at least one hydroxyphenyl derivative as defined above. The pharmaceutical compositions may be used to inhibit integrase, including HIV integrase, thus providing protection against HIV infection.
The expression “pharmaceutically effective amount” is to be understood herein as referring to an amount effective in treating HIV infection in a patient. The term prophylactically effective amount refers to an amount effective in preventing HIV infection in a patient. As used herein, the term patient refers to a mammal, including a human. The expressions “pharmaceutically acceptable carrier” (or adjuvant) and “physiologically acceptable vehicle” are to be understood as referring to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof. These factors will be discussed in more detail below.
The compounds of this invention may be readily prepared using conventional techniques from commercially available and cheap starting materials. The relative ease of synthesis of the products described in this invention represents a marked advantage for the large scale preparation of these compounds. In general, the derivatives of the present invention may be readily obtained from amino acids through sequences recognized by those knowledgeable in the art as straightforward, requiring readily available reagents and easy techniques. Using standard techniques, amino acids may be transformed to the desired HIV integrase inhibitors according to approaches as shown in Scheme 1, Scheme 2 and Scheme 3 which are discussed below. The preparation of dipeptide derivatives may be accomplished by solid phase peptide synthesis; this type of process is generically illustrated in scheme 4 below (see example 42 below).
Scheme 1 illustrates example steps for the preparation of a derivative in accordance with the present invention:
Note:
a) For scheme 1, PG and PG′ may be any suitable (known) removable protecting group for respectively protecting the amine functional group and the carboxylic acid functional group(s). PG may, for example, be Boc i.e. tert-butoxycarbonyl and PG′ may, for example, be tert-Butyl, 2,6-Cl 2 Bzl or Bzl, i.e. a functional group of the following formula
b) For scheme 1 R 1 may, for example, be CH 3 —, BzlOOCCH 2 CH 2 —, H 2 NC(O)CH 2 CH 2 —; R 1a may, for example, be CH 3 —, HOOCCH 2 CH 2 —, H 2 NC(O)CH 2 CH 2 —
Step 1)
Step 2)
Step 3)
Step 4)
Step 5)
In accordance with Scheme 1, illustrated above, different pharmacophores may be attached to the amino acid via the N-terminal. Thus, for step 1 compound 1 is treated so as to protect the carboxylic acid functional group by means of a suitable protecting group PG′; for example compound 1 may be a Boc-amino acid which is benzylated with benzyl bromide to yield compound 2 in the form of a benzyl ester using cesium carbonate in DMF according to the method of S.-S. Wang et al (J. Org. Chem. vol 49 p. 1286 (1977)). For step 2 the amino protecting group PG is removed to provide compound 3 having a free amino functional group; for example the removal of the Boc group from compound 3 may be carried out by stirring in a mixture of TFA and methylene chloride (1:1 (v/v)). For step 3 the amino compound 3 is then coupled with an hydroxylated benzoic acid (compound 4) with EDC and HOBT in DMF providing the desired coupled product compound 5. For step 4 compound 5 is treated to remove the protecting group PG′ to yield compound 6 having a free carboxylic acid group; for example the benzyl protecting group PG′ may be removed by hydrogenolysis using 10% Pd/C as catalyst to yield compound 6 having a free carboxylic acid group. Finally for step 5 compound 6 is coupled with dopamine (compound 7) to provide the desired derivative, namely compound 8.
Scheme 2 (which is divided below into scheme 2a and scheme 2b) illustrates example steps for an alternate method for the preparation of a derivative in accordance with the present invention:
Note:
a) For scheme 2a, PG, as mentioned above, may be any suitable (known) removable protecting group for protecting the amine functional group. PG may, for example, be Boc i.e. tert-butoxycarbonyl
b) For scheme 2a, R 3 may, for example, be (CH 3 ) 2 CHCH 2 —, CH 3 SCH 2 CH 2 —, or a functional group of the following formula
Scheme 2a:
Step 1
Step 2:
Step 3:
Scheme 2b:
Step 1
Step 2:
Step 3:
The second approach illustrated in scheme 2 above proceeds by the C-terminal first with the subsequent coupling taking place at a later stage after the removal of the amino blocking group. Thus, for step 1 of scheme 2a compound 1 (e.g. a Boc amino acid) is coupled with dopamine (compound 9) using EDC and HOBT as coupling reagents in DMF to obtain compound 10. For step 2 of scheme 2a compound 10 is treated to remove the protecting or blocking group PG to obtain compound 11; for example, the removal of a Boc group may be performed by stirring compound 10 in a mixture of TFA and methylene chloride at room temperature for a short period of time. For step 3 of scheme 2a compound 11 may then be coupled with the appropriate hydroxybenzoic acid (compound 4) using the EDC/HOBT coupling conditions to obtain compound 12. The desired product compound 12 may then be deprotected if needed or appropriate by hydrogenolysis using 10% Pd/C as catalyst for those amino acid with functionality on the side chain. Scheme 2b may proceed in an analogous fashion.
Scheme 3 illustrates yet another example method for the preparation of a derivative in accordance with the present invention
Note:
a) For scheme 3, PG and PG″ may be any suitable (known) independently removable protecting group for respectively protecting different functional groups including a nitrogen atom. PG may, for example, be Boc i.e. tert-butoxycarbonyl and PG″ may, for example, be Fmoc, i.e. 9-fluorenylmethoxycarbonyl
b) For scheme 3, R 4 may, for example, be —HNCH 2 CH 2 CH 2 — or a group of formula
and R 5 may, for example, be H 2 NCH 2 CH 2 CH 2 — or a group of formula
Step 1
Step 2
Step 3:
Step 4:
In scheme 3 illustrated above the starting amino acid (compound 13) is provided with a pair of independently removable protecting groups PG and PG″; the amino group may have a protecting group (PG″) such as Fmoc for example. On the other hand if the group R 4 includes a primary or secondary amino component a protecting group PG may likewise be attached to the nitrogen atom of such an amino component; PG may, for example, be Boc or tert-butoxycarbonyl. Thus, for step 1 of scheme 3 compound 13 is coupled with dopamine (compound 9) using EDC and HOBT as coupling reagents in DMF to obtain compound 14. For step 2 compound 14 is treated to remove the protecting or blocking group PG″ to obtain compound 15. For step 3 compound 15 may then be coupled with the appropriate hydroxybenzoic acid (compound 4) using the EDC/HOBT coupling conditions to obtain compound 16. For step 4 compound 15 is treated to remove the protecting group PG to yield compound 17.
Scheme 4 illustrates in a generic fashion an example method for the preparation of a dipeptide derivative in accordance with the present invention (see example 42 below for a more specific description of a process for making a dipeptide derivative):
Step 1
(RX and RX′ independently have the values set forth for R herein).
The compounds listed in Table 1 were prepared by following Scheme 1 or Scheme 2 (see examples below); the number(s) in brackets after each root amino acid name is the numer(s) of an example(s) below. Their activities are also listed in the same table demonstrating their potential usefulness.
TABLE 1
Anti-integrase activity (IC 50 ) of amino acid derivatives in accordance with
formula Ic above
Anti-integrase activity (IC 50 )
Root Amino acid
4-hydroxy
3,4-dihydroxy
(i.e. W for formula I is the fragment
derivative
derivative
thereof)
μM
μM
Glycine (ex. 15)
100
L-Glutamic (ex. 21 & 22 - step B)
64
11
L-Glutamic-4-O-benzyl (ex. 23)
26
L-Tyrosine (ex. 11 & 12)
88
8
L-Tryptophan (ex. 29 & 30)
245
17
L-Proline (ex. 27 & 28)
>200
80
L-Leucine (ex. 25 & 26)
>200
45
L-Phenylalanine (ex. 13 & 14)
>200
45
L-Serine (ex. 18)
100
L-Methionine (ex. 31)
100
L-Dopa (ex. 16)
8
D-Tyrosine (ex. 10)
67
D-Tyrosine-O-benzyl (ex. 10 - step D)
42
L-Alanine (ex. 19 & 20)
160
71
L-Histidine (ex. 33)
0.1
DL-3-Fluoro-Tyrosine (ex. 48)
1.4
L-Glutamine benzyl ester (ex. 49)
2.2
DL-m-Tyrosine (ex. 50)
1.3
Dipeptide derivatives were also prepared and are listed in Table 2; the number(s) in Table 2 with respect to each product structure name therein indicated a number of an example.
TABLE 2
Anti-integrase activity (IC 50 ) of dipeptide derivatives of I
Anti-
integrase
activity
Product
Xa
Y
(IC 50 )
Ex. No.
Xa-Tyr-
3,4-
OH
177
36
Tyr-Y
dihydroxybenzoyl
Xa-Tyr-
3,4-
3,4-dihydroxy-
17
51
Tyr-Y
dihydroxybenzoyl
phenethylamino
Xa-Gly-
3,4-
OH
>200
39
Tyr-Y
dihydroxybenzoyl
Xa-Tyr-
3,4-
3,4-dihydroxy-
20
41
Asp
dihydroxybenzoyl
phenethylamino
(OBn)-Y
Xa-Tyr-
3,4-
OH
>200
37
Gly-Y
dihydroxybenzoyl
As can be appreciated by the skilled artisan, the above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art.
For the purposes of Table 1 (and Table 2) the HIV-1 integrase inhibition assay was carried out following a known procedure (Burke, Jr. T. R. et al., J. Med. Chem. 38, 4171-4178 (1995)). A suitable radiolabeled duplex substrate corresponding to the U5 end of the HIV LTR was used.
The novel compounds of the present invention are excellent ligands for integrase, particularly HIV-1, and most likely HIV-2 and HTLV-1 integrase. Accordingly, these compounds are capable of targeting and inhibiting an early stage event in the replication, i.e. the integration of viral DNA into the human genome, thus preventing the replication of the virus.
In addition to their use in the prophylaxis or treatment of HIV infection, the compounds according to this invention may also be used as inhibitory or interruptive agents for other viruses which depend on integrases, similar to HIV integrases, for obligatory events in their life cycle. Such compounds inhibit the viral replication cycle by inhibiting integrase. Because integrase is essential for the production of mature virions, inhibition of that process effectively blocks the spread of virus by inhibiting the production and reproduction of infectious virions, particularly from acutely infected cells. The compounds of this invention advantageously inhibit enzymatic activity of integrase and inhibit the ability of integrase to catalyze the integration of the virus into the genome of human cells.
The compounds of this invention may be employed in a conventional manner for the treatment or prevention of infection by HIV and other viruses which depend on integrases for obligatory events in their life cycle. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques. For example a compound of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a virally infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the viral infection. Also, a compound of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against viral infections, such as HIV infection. As such, the novel integrase inhibitors of this invention can be administered as agents for treating or preventing viral infections, including HIV infection, in a mammal. The compounds of this invention may be administered to a healthy or HIV-infected patient either as a single agent or in combination with other antiviral agents which interfere with the replication cycle of HIV. By administering the compounds of this invention with other antiviral agents which target different events in the viral replication cycle, the therapeutic effect of these compounds is potentiated. For instance, the co-administered antiviral agent can be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA. Antiviral agents targeting such early life cycle events include, didanosine (ddI), zalcitabine (ddC), stavudine (d4T), zidovudine (AZT), polysulfated polysaccharides, sT4 (soluble CD4)—which blocks attachment or adsorption of the virus to host cells—and other compounds which block binding of virus to CD4 receptors on CD4-bearing T-lymphocytes. Other retroviral reverse transcriptase inhibitors, such as derivatives of AZT, may also be co-administered with the compounds of this invention to provide therapeutic treatment for substantially reducing or eliminating viral infectivity and the symptoms associated therewith. Examples of other antiviral agents include ganciclovir, dideoxycytidine, trisodium phosphonoformiate, eflornithine, ribavirin, acyclovir, alpha interferon and trimenotrexate. Additionally, non-ribonucleoside inhibitors of reverse transcriptase, such as TIBO or nevirapine, may be used to potentiate the effect of the compounds of this invention, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral protease. These compounds may also be co-administered with other inhibitors of HIV integrase.
Combination therapies according to this invention exert a synergistic effect in inhibiting HIV replication because each component agent of the combination acts on a different site of HIV replication. The use of such combinations also advantageously reduces the dosage of a given conventional anti-retroviral agent that would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy. These combinations may reduce or eliminate the side effects of conventional single anti-retroviral agent therapies while not interfering with the anti-retroviral activity of those agents. These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity. These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity. Preferred combination therapies include the administration of a compound of this invention with AZT, 3TC, ddI, ddC or d4T.
Alternatively, the compounds of this invention may also be co-administered with other HIV protease inhibitors such as Ro 31-8959 (Roche), L-735,524 (Merck), XM 323 (Dupont Merck) and A-80,987 (Abbott) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species.
We prefer administering the compounds of this invention as single agents or in combination with retroviral reverse transcriptase inhibitors, such as derivatives of AZT or HIV aspartyl protease inhibitors. We believe that the co-administration of the compounds of this invention with retroviral reverse transcriptase inhibitors or HIV aspartyl protease inhibitors may exert a substantial synergistic effect, thereby preventing, substantially reducing, or completely eliminating viral infectivity and its associated symptoms.
The compounds of this invention can also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbante, tumor necrosis factor, naltrexone and rEPO); antibiotics (e.g., pentamidine isethionate) or vaccines to prevent or combat infection and disease associated with HIV infection, such as AIDS and ARC.
When the compounds of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical or prophylactic compositions according to this invention may be comprised of a combination of an integrase inhibitor of this invention and another therapeutic or prophylactic agent.
Although this invention focuses on the use of the compounds disclosed herein for preventing and treating HIV infection, the compounds of this invention can also be used as inhibitory agents for other viruses that depend on similar integrases for obligatory events in their life cycle. These viruses include, but are not limited to, other diseases caused by retroviruses, such as simian immunodeficiency viruses, HTLV-I and HTLV-II.
Pharmaceutical compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmacentically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethyleneglycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of this invention may be administered orally, parenterally by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solutions. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv. or a similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspension and solutions. In the case of tablets for oral and carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable neat formulation. Topically-transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
Dosage levels of between about 0.01 and about 25 mg/kg body weight per day, preferably between about 0.5 and about 25 mg/kg body weight per day of the active ingredient compound are useful in the prevention and treatment of viral infection, including HIV infection. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. A typical preparation will contain from about 5% to about 75% active compound (w/w). Preferably, such preparations contain from about 20% to about 50% active compound.
Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment should cease, at least in principle. Patients may, however, require intermittent treatment on a long-term basis, upon any recurrence of disease symptoms, especially for AIDS.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the infection, the patient's disposition to the infection and the judgment of the treating physician.
The compounds of this invention are also useful as commercial reagents which effectively bind to integrases, particularly HIV integrase. As commercial reagent, the compounds of this invention, and their derivatives, may be used to block integration of a target DNA molecule by integrase, or may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications. These and other uses which characterize commercial integrase inhibitors will be evident to those of ordinary skill in the art.
DETAILED DESCRIPTION OF THE INVENTION
In order that the invention herein described may be more fully understood, the following detailed description is set forth. In the description, the following abbreviations are used:
Designation
Reagent or Fragment
Et
ethyl
Trityl
triphenylmethyl
Ala
DL, D-or L-alanine
Asn
DL, D-or L-asparagine
Cys
DL, D-or L-cysteine
Gly
glycine
Gln
DL, D-or L-glutamine
His
DL, D-or L-histidine
Ile
DL, D-or L-isoleucine
Leu
DL, D-or L-leucine
Met
DL, D-or L-methionine
Phe
DL, D-or L-phenylalanine
Pro
DL, D-or L-proline
Ser
DL, D-or L-serine
Thr
DL, D-or L-threonine
Trp
DL, D-or L-tryptophan
Val
DL, D-or L-valine
Boc
tert-butoxycarbonyl
EDC
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
BOP
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate
TFA
trifluoroacetic acid
EtOAC
ethyl acetate
DMF
dimethylformamide
AZT
zidovudine
IL-2
interleukin-2
rEPO
recombinant erythropoietin
EtOH
ethyl alcohol
MeOH
methyl alcohol
THF
tetrahydrofuran
CH 2 Cl 2
dichloromethane
Cl 2 -Bzl
2,6-dichlorobenzyl
tert-Bu
tert-butyl
Bzl
benzyl
NMP
N-methylpyrrolidone
CHCl 3
chloroform
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.
The term stable, as used herein, refers to compounds which possess stability sufficient to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
EXAMPLES
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.
Materials and Methods
Analytical thin layer chromatography (TLC) was carried out with 0.25 mm silica gel E. Merck 60 F 254 plates and eluted with the indicated solvent systems. Preparative chromatography was performed by flash chromatography, using silica gel 60 (EM Science) with the indicated solvent systems and a positive nitrogen pressure to allow proper rate of elution. Detection of the compounds was carried out by exposing eluted plates (analytical or preparative) to UV light and/or treating analytical plates with a 2% solution of p-anisaldehyde in ethanol containing 3% sulfuric acid and 1% acetic acid followed by heating.
Unless otherwise indicated, all starting materials were purchased from a commercial source such as Aldrich Co. or Sigma Co.
Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AMX 500 equipped with a reversed or QNP probe. Samples were dissolved in deuterochloroform (CDCl 3 ), deuteroacetone (acetone-d 6 ) or deuterodimethylsulfoxide (DMSO-d 6 ) for data acquisition using tetramethylsilane as internal standard. Chemical shifts are expressed in parts per million (ppm), the coupling constants (J) are expressed in hertz (Hz) whereas multiplicities are denoted as s for singlet, d for doublet, dd for doublet of doublets, t for triplet, q for quartet, m for multiplet, and br s for broad singlet.
GENERAL PROCEDURES
Example 1
Preparation of N-(tert-butoxycarbonyl)amino Acids
To a solution of amino acid (1 eq.) in water and dioxane were added at room temperature triethylamine (1.3-1.5 eq.) and Boc-ON (1.1 eq.) or di-tert-butyl-dicarbonate (2 eq.). The mixture was stirred at room temperature under argon for 3 to 5 h. The solution was diluted with water and extracted by ether at least six times. The aqueous layer was acidified to pH ˜2.5 with cold 1N HCl to yield an oily layer. The mixture was extracted three times with methylene chloride. The combined organic extracts were washed with brine and dried over magnesium sulfate. After filtration, the filtrate was evaporated using a bath set at 30° C. The residue was found to be of sufficient purity for the next reaction step.
Example 2
Benzylation of N-Boc Amino Acid
Three different solvent systems were used to achieve benzylation of acids or hydroxyl groups.
a) Methanol/Water Followed by DMF Method
To a N-Boc amino acid (1 eq.) in methanol was added cesium carbonate (1.4-2.0 eq.) as a 20% solution in water, and then the solution was evaporated to dryness. The residue was dissolved in dimethylformamide (DMF) and benzyl bromide (1-1.5 eq.) was added. The mixture was stirred at room temperature under argon overnight. The mixture was diluted with water and the organic layer was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over magnesium sulfate. The solids were filtered off and solvent was evaporated under vacuum yielding a residue that was purified by silica gel chromatography using 20% ethyl acetate in hexane.
b) Dimethylformamide Method
To a N-Boc amino acid (1 eq.) in dimethylformamide (DMF) were added cesium carbonate (1.4-2.0 eq.) and benzyl bromide (1.1-1.5 eq.). The reaction mixture was stirred at room temperature overnight under argon. A work-up and purification as previously described in example 2a yielded the desired product.
c) Acetone Method
To a N-Boc amino acid (1 eq.) in acetone were added potassium carbonate (1.4-2.0 eq.) and benzylbromide (1.1-1.5 eq.). The reaction mixture was stirred at room temperature for a period of 3-5 h under argon. Work-up and purification as carried out in the previous example 2a afforded the desired product.
Example 3
Removal of the N-tert-butoxycarbonyl (Boc) Group
A solution of N-tert-butoxycarbonyl amino acid (1 eq.) in a 1: 1 mixture of trifluoroacetic acid (TFA) (10 eq.) and methylene chloride (CH 2 Cl 2 ) was stirred at room temperature for 15-30 min. The solvent and excess acid were removed under vacuum to yield the desired product that was used without further purification.
Example 4
Coupling Reaction of Hydroxylated Benzoic Acid With the NH Part of an Amino Acid
To a mixture of 3-hydroxy- or 3,4-dihydroxybenzoic acid (1.5 eq.), hydroxybenzotriazole hydrate (HOBT) (1.6 eq.), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (1.6 eq.) in DMF was added a solution of product from example 3 (1 eq.) and triethylamine or diisopropylethylamine (1 eq.) in DMF. The mixture was stirred at room temperature under argon for either 6 h or overnight, monitoring the reaction by TLC. The reaction mixture was quenched by water and extracted three times with ethyl acetate. The organic phases were combined and washed with brine. After drying over magnesium sulfate, the solution was filtered and the solvent was evaporated under vacuum. The residue was purified by silica gel chromatography, eluting as indicated in each procedure.
Example 5
Cleavage of Benzyl Esters or Benzyl Ethers
The benzyl ester or benzyl ether of an amino acid derivative dissolved in methanol was hydrogenated over 10% Pd—C (less than 10% by weight of the weight the amino acid benzyl ester or ether) under 1 atmosphere of H 2 for 1-2 h. The catalyst was filtered off and the filtrate was evaporated under vacuum to yield the desired product.
Example 6
Coupling Reaction of Dopamine With the COOH of a Substituted Amino Acid
To a solution of substituted carboxylic acid (1 eq.) prepared as in example 5, HOBT (1.5 eq.) and EDC (1.5 eq.) in DMF at 0° C. was added a solution of dopamine hydrochloride (2 eq.) and triethylamine or diisopropylethylamine (2 eq.) in DMF. The mixture was stirred under argon for 0.5 h and the mixture was allowed to reach room temperature and stirred overnight. The resulting mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined and washed with brine. After drying over magnesium sulfate, the solution was filtered and the solvent was evaporated under vacuum. The residue was purified by silica gel chromatography, eluting agent as indicated in each procedure.
Example 7
Removal of the N-9-fluorenylmethoxycarbonyl (Fmoc) Group
A solution of N-(9-fluorenylmethoxycarbonyl) amino acid (1 eq.) in 30% diethylamine in acetonitrile was stirred 15 min at room temperature. The solvent was removed under vacuum to yield the desired product that was used without further purification.
Example 8
Removal of the Methyl Ester group
Amino acid methyl ester (0.2 eq.) was dissolved in methanol at room temperature 1N sodium hydroxide (0.65 mL) was added, the mixture was stirred for 0.5 h and 1N HCl (0.3 mL) was added, maintaining the temperature at around 0° C. After removing the methanol under vacuum, a second portion of 1N HCl (0.3 mL) was added to adjust the pH at ˜2.5. The organic acid was extracted with CH 2 Cl 2 , dried over magnesium sulfate and concentrated in vacuo, yielding the desired product that was used for the next step without further purification.
Example 9
Coupling Reaction of Hydroxylated Benzoic Acid With the NH Part of an Amino Acid Using BOP Reagent
The acid (0.1M in a 1-1 mixture of dioxan and dichloromethane) and BOP reagent (1.0 eq.) was stirred at room temperature under an inert atmosphere. The amine (1.2 eq.) was directly added followed by the base (triethylamine, 1.2 eq.). The reaction was stirred for 3 to 16 h. The suspension was then poured in an extraction vessel containing ethyl acetate and 1N hydrochloric acid and the organic layer washed with 3 portions of water before drying over magnesium sulfate. The solution was filtered and concentrated in vacuo before purification by flash chromatography.
Specific Examples for the Preparation of Derivatives in Accordance With the Present Invention
Example 10
Preparation of the N-[N′-(3′,4′-dihydroxybenzoyl)-D-tyrosyl]-dopamine
Step A. Preparation of N-(tert-butoxycarbonyl)-D-tyrosine
The title compound was prepared from D-tyrosine (543 mg, 3.0 mmol), by following the procedure described in example 1. The product was isolated as a colorless syrup (740 mg, 88% yield).
1 H NMR (DMSO-d 6 ): 1.32 (s, 9H); 2.71 (dd, J=3.3, 12.9, 1H); 2.89 (dd, J=3.8, J=12.3, 1H); 4.00 (m, 1H); 6.64 (d, J=8.6, 2H); 6.95 (d, J=8.0, 1H); 7.03 (d, J=8.6, 2H) 9.18 (br s, 1H); 12.46 (s, 1H).
Step B. Preparation of N-(tert-butoxycarbonyl)-O-benzyl-D-tyrosine benzyl ester
The title compound was prepared from the product obtained in step A of this example (650 mg, 2.3 mmol) according to the indications of example 2a. The crude product was purified by silica gel column chromatography using 5% MeOH/CHCl 3 to yield the desired product (650 mg, 61%).
1 H NMR (DMSO-d 6 ): 1.32 (s, 9H); 2.83 (dd, J=9.8, 13.5, 1H); 2.93 (dd, J=5.5, 13.8 1H); 4.17 (q, J=7.1, 8.3, 1H); 5.05 (s, 2H); 5.08 (s, 2H); 6.91 (d, J=8.2, 2H); 7.13 (d, J=8.2, 2H); 7.28-7.44 (m, 10H).
Step C. N-(3′,4′-dihydroxybenzoyl)-O-benzyl-D-tyrosine benzyl ester
The title compound was prepared from the product obtained in step B of this example (110 mg, 0.24 mmol) by the removal of the Boc group following the indications of example 3. The resulting unblocked derivative was then coupled with 3,4-dihydroxybenzoic acid according to the indications of example 4. The crude product was purified by silica gel column chromatography using 5% methanol/chloroform to yield the desired product as a white solid, mp. 140° C. (dec.), (88 mg, 74%).
1 H NMR (CDCl 3 ): 3.15 (m, 2H); 4.98 (s, 2H); 5.01 (m, 1H); 5.18 (m, 2H); 6.63 (d, J=7.4, 1H); 6.80 (d, J=7.4, 2H); 6.85 (d, J=8.9, 1H); 6.92 (d, J=7.4, 2H); 7.08 (d, J=7.4, 2H); 7.26 (s, 1H); 7.31-7.41 (m, 0H).
Step D. N-[N′-(3′,4′-dihydroxybenzoyl)-O-benzyl-D-tyrosyl]-dopamine
The title compound was prepared from the product of step C of this example (200 mg, 0.39 mmol) by removing the benzyl ester group following the indications of example 5. The resulting unblocked derivative was coupled with dopamine hydrochloride according to the indications of example 6. Purification by silica gel chromatography (3%MeOH/EtOAc) provided the desired product, (88 mg, 40%) as a white solid, mp. 131° C. (dec.).
1 H NMR (DMSO-d 6 ): 2.60 (m, 2H), 3.03 (dd, J=7.9, 13.7, 1H); 3.16 (dd, J=5.3, 14.2, 1H); 3.36 (m, 2H); 4.79 (m, 1H); 5.02 (s, 2H) 6.69 (d, J=7.9, 1H); 6.71 (s, 1H); 6.85 (d, J=7.9, 1H); 6.89 (d, J=8.8, 2H); 7.19 (d, J=6.1, 2H); 7.27 (t, J=6.7, 1H); 7.30 (s 1H); 7.34 (d, J=7.4, 1H); 7.30-7.47 (m, 5H); 7.58 (d, J =7.7, 1H); 8.04 (br s, 4H).
Step E N-[N′-(3′,4′-dihydroxybenzoyl)-D-tyrosyl]-dopamine
The title compound was prepared from the product of step D of this example (60 mg, 0.11 mmol) by following the indications in example 5. Purification by silica gel chromatography (100% EtOAc) provided the desired product, (21 mg, 43%) as a white solid, mp. 178° C. (dec.).
1 H NMR (DMSO-d 6 ): 2.60 (m, 2H); 2,89 (dd, J=8.0, 13.9, 1H); 3.11 (dd, J=5.5, 13.9, 1H); 3.36 (m, 2H); 4.74 (m, 1H); 6.50 (d, J=7.0, 1H); 6.68 (d, J=8.1, 1H); 6.72 (d, J=6.3, 1H); 6.73 (s, 1H); 6.83 (d, J=7.5, 1H); 7.11 (d, J=8.0, 2H); 7.38 (d, J=7.4, 2H); 7.26 (t, J=6.7, 1H); 7.48 (d, J=7.6, 1H); 8.04 (br s, 5H).
Example 11
Preparation of N-[N′-(p-hydroxybenzoyl)-L-tyrosyl]-dopamine
Step A. N-p-hydroxybenzoyl-O-tert-butyl-L-tyrosine tert-butyl ester
The title compound was prepared from O-tert-butyl-L-tyrosine tert-butyl ester (445 mg; 1.60 mmol) by following the indications of example 4. Purification by flash chromatography eluting with 20% ethyl acetate in hexane provided 291 mg (51%) of the title compound, mp. 106° C.
1 H NMR: (CDCl 3 ): 1.31 (s, 9H), 1.41 (s, 9H), 3.18 (d, J=5.6, 2H), 4.91 (m, 1H), 6.68 (d, J=7.3, 1H), 6.82 (d, J=8.0, 2H), 6.92 (d, J=8.3, 2H), 7.07 (d, J=8.0, 2H), 7.56 (d, J=8.3, 2H), 8.41 br s, 1H).
Step B. N-[N′-(p-benzoyl)-L-tyrosyl]-dopamine
The tert-butyl protecting group was removed by treatment of the product of step A of this example (21 mg, 0.05 mmol) with trifluoroacetic acid according to the conditions in example 3. The residue was treated without further purification with dopamine hydrochloride according to the procedure of example 6, providing the title product (16 mg, 53%), mp. 161° C.
1 H NMR (acetone-d 6 ): 2.52-2.61 (m, 2H), 2.95 (dd, J=14.4, 8.2, 1H), 3.10 (dd, J=14.4, 8.2, 1H), 3.27-3.37 (m, 2H), 4.71-4.76 (m, 1H), 6.47 (d, J=8.4, 1H), 6.63-6.7 (m, 4H), 6.82 (d, J=6.9, 2H), 7.07 (m, 2H), 7.38 (d, J=5.2, 1H), 7.54 (d, J=8.0, 1H), 7.69 (d, J=7.7, 2H), 7.4-7.9 (br s, 2H), 8.12 (br s, 1H).
Example 12
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-tyrosyl]-dopamine
Step A. N-3′,4′-dihydroxybenzoyl-O-tert-butyl-L-tyrosine tert-butyl ester
The title compound was prepared from O-tert-butyl-L-tyrosine tert-butyl ester (500 mg; 1.8 mmol) by following the indications of example 4. Purification by flash chromatography eluting with 10% methanol in methylene chloride provided 511 mg (80%) of the title compound, mp. 122° C.
1 H NMR: (CDCl 3 ):0.87 (s, 9H), 0.88 (s, 9H), 3.16 (m, 2H), 4.78 (d, J=7.5, 1H), 6.85 (d, J=9.1, 1H), 6.89 (d, J=8.5, 2H), 7.21 (d, J=8.5, 2H), 7.29 (d, J=9.1, 2H), 7.42 (s, 1H), 7.49 (d, J=7.5, 2H), 8.29 br s, 1H), 8.50 (br s, 1H).
Step B. N-[N′-(3′,4′-dihydroxybenzoyl)-L-tyrosyl]-dopamine
The tert-butyl protecting group was removed by treatment of the product of step A of this example (184 mg, 0.42 mmol) with trifluoroacetic acid according to the indications of example 3. The residue was treated without further purification with dopamine hydrochloride according to the procedure of example 6, providing the title product (128 mg, 66%), mp.205° C.
1 H NMR (acetone-d 6 ):2.56 (m, 2H), 2.99 (dd, J=13.6, 7.9, 1H), 3.11 (dd, J=13.6, 5.3, 1H), 3.36 (m, 2H), 4.78 (m, 1H), 6.46 (d, J=7.8, 1H), 6.64 (d, J=7.8, 1H), 6.68 s, 1H), 6.70 (d, J=8.3, 2H), 6.80 (d, J=8.6, 1H), 7.09 (d, J=8.3, 2H), 7.24 (d, J=8.6, 1H), 7.39 (s, 1), 7.55 (m, 1 H), 7.65 (d, J=7.6, 1H), 7.5-8.4 (br s, 5H).
Example 13
Preparation of N-[N′-(p-hydroxybenzoyl)-L-phenylalanyl]-dopamine
Step A. N-p-hydroxybenzoyl-L-phenylalanine benzyl ester
The title compound was prepared from L-phenylalanine benzyl ester (400 mg; 1.58 mmol) by following the indications of example 4. Purification by flash chromatography eluting with 10% ethyl acetate in hexane containing 1% acetic acid provided 323 mg (92%) of the title compound, mp. 163° C.
1 H NMR: (CDCl 3 ):3.16 (dd, J=12.8, 8.9, 1H), 3.24 (dd, J=12.8, 8.9, 1H), 4.92 (m, 1H), 5.12 (s, 2H), 6.83 (d, J=6.6, 2H), 7.15-7.31 (m, 10H), 7.70 (m, 3H), 8.90 (br s, 1H).
Step B. N-[N′-(p-benzoyl)-L-phenylalanyl]-dopamine
The product obtained in step A of this example (287 mg, 0.76 mmol) following the indications of examples 5 and 6, provided, after flash chromatography eluting with 50% ethyl acetate in dichloromethane containing 1% acetic acid, the desired product (301 mg, 94%), mp. 196° C.
1 H NMR (acetone-d 6 ): (two conformers) 2.48 (t, J=7.6, 2H), 2.60 (t, J=7.8, 2H), 2.93 (m, 1H), 3.00 (dd, J=13.3, 3.8, 1H), 3.13-3.25 (m, 1H), 3.32 (m, 1H), 4.59 (m, 1H), 6.41 (d, J=7.1, 1H), 6.57 (m, 2H), 6.76 (m, 2H), 7.12 (m, 1H), 7.21 (d, J=7.4, 2H), 7.26 (d, J=7.5, 1H), 7.65 (d, J=7.4, 2H), 8.00 (t, J=5.7, 1H), 8.21 (d, J=8.3 (1H), 8.59 (s, 1H), 8.69 (s, 1H), 9.92 (s, 1H).
Example 14
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-phenylalanyl]-dopamine
Step A. N-3,4-dihydroxybenzoyl-L-phenylalanine benzyl ester
The title compound was prepared from L-phenylalanine benzyl ester (400 mg; 1.57 mmol) by following the indications of example 4. Purification by flash chromatography eluting with 40% ethyl acetate in hexane containing 1% acetic acid provided 323 mg (60%) of the title compound, mp. 155° C.
1 H NMR: (CDCl 3 ):3.24 (dd, J=13.6, 8.5, 1H), 3.32 (dd, J=13.6, 5.2, 1H), 4.92 (m, 1H) 5.03 (m, 1H), 5.17 (s, 2H), 6.92 (d, J=8.0, 1H), 7.20-7.36 (m, 11H), 7.53 (s, 1H), 7.88 (d, J=7.3, 1H), 8.57 (br s, 1H).
Step B. N-[N′-(3′,4′-benzoyl)-L-phenylalanyl]-dopamine
The product obtained in step A of this example (18 mg, 0.046 mmol) following the indications of examples 5 and 6, provided after flash chromatography eluting with 50% ethyl acetate containing 1% acetic acid, the desired product (19 mg, 73%), mp. 201° C.
1 H NMR (acetone-d 6 ): 2.52-2.59 (m, 2H), 3.04 (dd, J=13.7, 7.7, 1H), 3.18 (dd, J=13.7, 7.7 1H), 3.32 (m, 2H), 4.77 (dt, J=6.3, 7.6, 1H), 6.45 (d, J=7.1, 2H, 7.11-7.26 (m, 6H), 7.34 (s, 1H), 7.38 (m, 2H), 7.52 (d, J=7.6, 1H), 7.98 (s, 4H).
Example 15
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-glycyl]-dopamine
Step A. N-(3,4-dihydroxybenzoyl)-glycine tert-butyl ester
The title compound was prepared from glycine tert-butyl ester (400 mg; 2.57 mmol) by following the indications of example 4. Purification by flash chromatography eluting with 40% ethyl acetate in hexane containing 1% acetic acid provided 337 mg (52%) of the title compound, mp. 139° C.
1 H NMR: (acetone -d 6 ): 1.52 (s, 9H), 4.09 (d, J=5.5, 2H), 6.95 (d, J=7.3, 1H), 7.42 (d, J=7.3, 1H), 7.55 (s, 1H), 7.90 (br s, 1H), 8.34 (br s, 1H), 8.60 (br s, 1H).
Step B. N-[N′-(3′,4′-benzoyl)-glycyl]-dopamine
The product obtained in step A of this example (277 mg, 1.03 mmol) following the indications of examples 3 and 6, provided, after flash chromatography eluting with 30% ethyl acetate in methylene chloride containing 1% acetic acid, the desired product (163 mg, 45%), mp. 155° C.
1 H NMR (acetone-d 6 ): 2.58 (t, J=7.1, 2H), 3.34 (dt, J=7.1, 5.1, 2H), 3.99 (d, J=5.3, 2H), 6.47 (d, J=8.0, 1H), 6.64 (d, J=8.0, 1 H), 6.67 (s, 1H), 6.85 (d, J=57.7, 1H), 7.31 (d, J=7.7, 1H), 7.44 (s, 1H), 7.47 (t, J=5.1, 1H), 7.94 (t, J=5.0, 1H), 7.4-8.0 (br s, 2H), 8.4 (br s, 2H).
Example 16
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-3,4-dihydroxy-phenylalanyl]-dopamine
Step A. N-(tert-butoxycarbonyl)-O,O′-dibenzyl-3,4-dihydroxyphenyl-L-alanine benzyl ester
The title compound was prepared from L-3,4-dihydroxyphenylalanine (DOPA) as described in examples 1 and 2b. In example 1, di-tert-butyl-dicarbonate (960 mg, 4.4 mmol) was used instead of Boc-ON to react with DOPA (790 mg, 4.0 mmol) with triethylamine (600 mg, 6.0 mmol) as base. The product was used for the next step without purification following the indications of example 2b, using 280 mg, (0.94 mmol). Purification by flash chromatography using 15% EtOAc/hexane provided the title compound as white crystals (180 mg, 34%), mp. 106-108° C.
1 H NMR (CDCl 3 ): 1.41 (s, 9H); 3.00 (d, J=4.9, 2H); 4.14 (s, 1H); 4.94 (d, J=7.4, 1H); 5.04-5.10 (m, 6H); 6.57 (d, J=7.8, 1H); 6.78 (d, J=8.4, 1H); 6.71 (s, 1H); 7.26-7.43 (m, 15H).
Step B. N-(3′,4′-dihydroxybenzoyl)-O,O′-(dibenzyl)-L-3,4-dihydroxyphenylalanine benzyl ester
The title compound was prepared by cleaving the Boc protecting group of the product prepared in step A of this example (130 mg, 0.23 mmol) and coupling it with 3,4-dihydroxybenzoic acid as described in example 3 and in example 4 respectively. Purification by flash chromatography using 5% MeOH/CHCl 3 yielded the desired product as a white solid (86 mg, 60%), mp. 215° C. (dec.).
1 H NMR (CDCl 3 ): 3.11 (m, J=6.1, J=14.1, 1H); 3.14 (dd, J=6.7, 13.9, 1H); 5.00 (s, 1H); 5.06-5.13 (m, 6H); 6.53 (d, J=8.0, 1H); 6.65 (d, J=7.6, 1H); 6.69 (s, 1H); 6.76 (d, J8.2, 1H); 6.82 (d, J=8.1, 1H); 7,05 (d, J=8.0, 1H); 7.25-7.47 (m, 15H); 7.47 (s, 1H).
Step C. N-(3′,4′-dihydroxybenzoyl)-L-3,4-dihydroxyphenylalanine
The title compound was prepared by the reduction of the compound obtained in step B of this example (64 mg, 0.11 mmol) according to the indications found in example 5. The product was purified by flash chromatography eluting with 10% MeOH/EtOAc, affording the desired product as a solid (27 mg, 73% yield), mp. 121° C. (dec.).
1 H NMR (DMSO-d 6 ): 2.98 (m, 2H); 4.44 (m, 1H); 6.53 (d, J=7.9, 1H); 6.59 (d, J=7.6, 1H); 6.66 (s, 1H); 6.75 (d, J=8.2, 1H); 7,17 (d, J=7.9, 1H); 7.24 (s, 1H); 8.14 (d, J=8.2, 1H); 8.69 (s, 2H), 9.11 (s, 2H); 12.50 (s, H).
Step D. N-[N′-(3′,4′-dihydroxybenzoyl)-L-3,4-dihydroxylphenylalanyl]-dopamine
The product from step C of this example was coupled with dopamine hydrochloride according to the procedure of example 6. Finally the O-benzyl ether protecting groups were hydrogenolyzed by following the indications of example 5. Purification by flash chromatography using 5% MeOH/EtOAc yielded the desired product (13.8 mg, 28%), mp. 142° C. (dec.).
1 H NMR (DMSO-d 6 ): δ2.48 (m, 2H); 2.67 (m, 2H); 3.32 (m, 2H); 4.47 (m, J=4.3, J =9.1, 1H); 6.42 (d, J=7.0, 1H); 6.51 (d, J=7.4, 1H); 6.58 (d, J=7.5, 1H); 6.59 (d, J=8.4, 1H); 6.66 (s, 1H); 6.74 (d, J=7.7, 1H); 7,15 (s, 1H); 7,17 (d, J=7.6, 1H); 7.22 (s, 1 H); 7.93 (t, J=5.7, 1H); 7.95 (d, J=8.5, 1H); 8.67 (br s, 6H, OH).
Example 17
Preparation of N-[′-(3′,4′-dihydroxybenzoyl)-trans-4-hydroxyprolyl]-dopamine
Step A. N-(tert-butoxycarbonyl)-O-benzyl-trans-4-hydroxy-L-proline benzyl ester
The title compound was prepared from trans-4-hydroxyproline as described in example 1 and 2b. The Boc derivative was prepared with the following quantities: di-tert-butyl-dicarbonate (960 mg, 4.4 mmol), trans-4-hydroxyproline (260 mg, 2.0 mmol), triethylamine (300 mg, 3.0 mmol). The product was used for the next step without purification. The benzylation was performed according to the indications of example 2 b. Purification by flash chromatography using 20% EtOAc/hexane provided the title compound as syrup (368 mg, 48%).
1 H NMR (CDCl 3 ): 1.35 and 1.45 (s, 9H); 2.06 (m, 1H); 3.62 (m, 1H); 3.72 (m, 1H); 4.41 (t, J=7.4, 1H);4.51 (m, 1H); 5.15 (s, 4H); 7.34-7.37 (m, 10H).
Step B. N-(3,4-dihydroxybenzoyl)-O-benzyl-trans-4-hydroxy-L-proline benzyl ester
The title compound was prepared by cleaving the Boc group of the compound obtained in step A of this example (350 mg, 0.85 mmol) by following the indications of example 3, and coupling it with 3,4-dihydroxybenzoic acid (196 mg, 1.27 mmol) according to example 4. Purification by flash chromatography using 5% MeOH/CHCl 3 , provided the desired product as an oil (275 mg, 72.4% yield).
1 H NMR (DMSO-d 6 ): 2.02 (m, 1H); 2.24 (m, 1H); 3.79 (d, J=8.4,1H); 3.96 (d, J=10.1, 1H); 4.18 (s, 1H); 4.59 (t, J=8.4, 1H); 5.16 (s, 4H); 6.77 (d, J=7.9, 1H); 6.87 (d, J=7.7, 1H); 6.98 (s, 1H); 7.31-7.37 (m, 10H); 9.22 (br s, 1H); 9.42 (br s, 1H).
Step C. N-[N′-(3′, 4′-dihydroxybenzoyl)-O-benzyl-trans-4-hydroxyprolyl]-dopamine
The title compound was prepared from the product obtained in step B of this example (420 mg, 1.0 mmol) by removal of the benzyl ester group as described in example 5. The resulting acid was then coupled with dopamine hydrochloride as described in example 6. Flash chromatography eluting with 1% MeOH/EtOAc provided the desired product as a syrup (100 mg, 20%).
1 H NMR (DMSO-d 6 ): 1.88 (m, 1H); 2.28 (m, 1H); 2.53 (m, 2H); 3.16 (m, 2H); 3.58 (d, J=11, 1H); 3.73 (d, J=8.9, 1H); 4.11 (s, 1H) 4.35 (m, 2H); 4.48 (t, J=7.7, 1H); 6.44 (d, J=7.7, 1H); 6.58 (s, 1H); 6.62 (d, J=8.2, 1H); 6.77 (d, J=8.2, 1H); 6.90 (d, J=7.9, 1H); 7.00 (s, 1H); 7.21-7.30 (m, 5H); 7.95 (t, J=5.3, 1H); 8.62 (br s, 1H); 8.72 (br s, 4H); 9.16 (br s, 1H); 9.37 (br s, 1H).
Step D. N-[N′-(3′,4′-dihydroxybenzoyl)-trans-4-hydroxyprolyl]-dopamine
The title compound was prepared from the compound of step C of this example (30 mg, 0.06 mmol) by following the indications of example 5. Purification by flash column chromatography with 3% MeOH/EtOAc afforded the desired product (18 mg, 75%) as white crystals, mp. 59-62° C.
1 H NMR (DMSO-d 6 ): 1.81 (m, 1H); 2.04 (m, 1H); 2.51 (m, 2H); 3.17 (m, 2H); 3.34 (d, J=6.6, 1H); 3.69 (d, J=8.3, 1H); 4.21 (s, 1H); 4.47 (t, J=8.3, 1H); 6.44 (d, J=6.7, 1H); 6.58 (s, 1H); 6.61 (d, J=7.7, 1H); 6.76 (d, J=8.2, 1H); 6.90 (d, J=8.0, 1H); 7.01 (s, 1 H); 8.90 (br s, 4H); 7.90 (t, J=5.3, 1H).
Example 18
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-seryl]-dopamine
Step A. N-(tert-butoxycarbonyl)-O-benzyl-L-serine benzyl ester
The title compound was prepared from N-(tert-butoxycarbonyl)-O-benzyl-L-serine, (300 mg, 1.0 mmol) as described in example 2b. Purification by flash chromatography eluting with 25% EtOAc/hexane provided the title compound as a syrup (370 mg, 96%).
1 H NMR (CDCl 3 ): 1.38 (s, 9H); 3.68 (m, 2H); 4.33 (q, J=6.2, J=6.0, 1H); 4.48 (m, 2H); 5.16 (m, 2H); 7.33 (m, 10H).
Step B. N-(3,4-dihydroxybenzoyl)-O-benzyl-L-serine benzyl ester
The title compound was prepared by cleaving the Boc group of the compound obtained in step A of this example (325 mg, 0.84 mmol) and coupling it with 3,4-dihydroxybenzoic acid as described in examples 3 and 4 respectively. Purification by flash chromatography eluting with 5% MeOH/CHCl 3 provided the desired product (220 mg, 62%).
1 H NMR (DMSO-d 6 ): 3.83 (m, 2H); 4.52 (m, 2H); 4.74 (q, J=6.3, J=6.4, 1H); 5.16 (m, 2 H); 6.78 (d, J=8.4, 1H); 7.26 (d, J=8.6, 1H); 7.28 (s, 1H); 7.29-7.32 (m, 10H); 8.42 (d, J=7.4, 1H); 9.15 (br s, 1H); 9.50 (br s, 1H).
Step C. N-[N′-(3′, 4′-dihydroxybenzoyl)-O-benzyl-L-seryl]-dopamine
The title compound was prepared from the compound obtained in step B of this example (160 mg, 0.38 mmol) according to the procedures described in example 5 and 6 respectively. Purification by flash chromatography eluting with 2.5% MeOH/EtOAc provided the desired product (68 mg, 37%).
1 H NMR (DMSO-d 6 ): 2.52 (m, 2H); 3.19 (m, 2H); 3.69 (d, J=6.1, 2H); 4.49 (s, 2H); 4.64 (q, J=5.6, J=6.4, 1H); 6.42 (d, J=7.6, 1H); 6.57 (s, 1 H); 6.60 (d, J=8.2, 1H); 6.77 (d, J=8.3, 1H); 7.23 (d, J=7.2, 1H); 7.25 (s, 1H); 7.29-7.327 (m, 5H); 8.01 (d, J=7.9, 1H); 8.02 )t, J=5.4, 1H); 8.62 (br s, 1H); 8.72 (br s, 1H); 9.12 (br s, 1H); 9.47 (br s,1H).
Step D. N-[N′-(3′, 4′-dihydroxybenzoyl)-L-seryl]-dopamine
The title compound was prepared from the compound obtained in step C of this example as described in example 5. The product was purified by flash chromatography eluting with 5% MeOH/EtOAc to provide the product (66%) as a solid, mp. 118° C. (dec.).
1 H NMR (DMSO-d 6 ): 2.51 (m, 2H); 3.17 (m, 2H); 3.66 (d, J=6.0, 2H); 4.39 (q, J=5.7, J=6.5, 1H); 6.43 (d, J=7.9, 1H); 6.57 (s, 1H); 6.59 (d, J=7.9, 1H); 6.79 (d, J=8.5, 1H); 7.25 (d, J=7.8, 1H); 7.32 (s, 1H); 7.86 (d, J=7.8, 1H); 7.95 (t, J=5.4, 1H); 9.00 (br s, 5H).
Example 19
Preparation of N-[N′-(p-hydroxybenzoyl)-L-alanyl]-dopamine
Step A. N-(tert-butoxycarbonyl)-L-alanine benzyl ester
The title compound was prepared from N-(tert-butoxycarbonyl)-L-alanine (567 mg, 3.0 mmol) as described in example 2a. Purification by flash chromatography eluting with 20% EtOAc/hexane provided the desired product as a syrup (800 mg, 96%).
1 H NMR (CDCl 3 ): 1.38 (d, J=7.3); 1.43 (s, 9H); 4.36 (s, 1H); 5.07 (s, 1H); 5.15 (m, 2H); 7.35 (s, 5H).
Step B. N-(p-hydroxybenzoyl)-L-alanine benzyl ester
The title compound was prepared from the product prepared in step A of this example (400 mg, 1.4 mmol) by removing the Boc group following the indications of example 3. The resulting product was then coupled with p-hydroxybenzoic acid according to example 4. Purification by flash chromatography eluting with 5% MeOH/CHCl 3 provided the desired product as white crystals (270 mg, 64%), mp. 82-84° C.
1 H NMR (DMSO-d 6 ): 1.40 (d, J=7.1, 3H); 4.49 (m, 1H); 5.13 (s, 2H); 6.80 (d, J=8.2, 2H); 7.35 (s, 5H); 7.75 (d, J=8.4, 2H); 8.53 (d, J=6.8, 1H); 9.99 (s, 1H).
Step C. N-[N′-(p-hydroxybenzoyl)-L-alanyl]-dopamine
The title compound was prepared from the compound obtained in step B of this example (150 mg, 0.50 mmol) following the indications of examples 5 and 6 for the cleavage of the benzyl ester and the coupling with dopamine hydrochloride. Purification by flash chromatography eluting with 5% MeOH/EtOAc provided the desired product (147 mg, 85%), mp. 127° C. (dec.).
1 H NMR (acetone-d 6 ): 1.28 (d, J=7.1, 3H); 2.51 (m, 2H); 3.17 (m, 2H), 4.40 (m, 1H); 6.43 (d, J=7.8, 1H); 6.57 (s, 1H); 6.59 (d, J=8.0, 1H); 6.80 (d, J=8.0, 2H); 7.77 (d, J=7.9, 2H); 7.86 (t, J=5.1, 1H); 8.12 (d, J=7.4, 1H); 8.16 (s, 1H); 8.71 (s, 1H); 9.95 (s, 1H).
Example 20
Preparation of N-[N′-(3′, 4′-dihydroxybenzoyl)-L-alanyl]-dopamine
Step A. N-(3,4-dihydroxybenzoyl)-L-alanine benzyl ester
The title compound was prepared from N-(tert-butoxycarbonyl)alanine benzyl ester (400 mg, 1.4 mmol) by the removal of the Boc group following the indications of example 3. The resulting compound was then coupled with 3,4-dihydroxybenzoic acid according to indications of example 4. Purification by flash chromatography eluting with 5% MeOH/CHCl 3 provided the desired product as a syrup (180 mg, 41%).
1 H NMR (DMSO-d 6 ): 1.40 (d, J=7.1, 3H); 4.47 (m, 1H); 5.13 (s, 2H); 6.78 (d, J=8.2, 1H); 7.24 (d, J=7.9, 1H); 7.32 (s, 1H); 7.35 (s, 5H); 8.47 (d, J=6.7, 1H); 9.12 (s, 1H), 9.48 (s, 1H).
Step B. N-[N′-(3′, 4′-dihydroxybenzoyl)-L-alanyl]-dopamine
The title compound was prepared from the compound of step A of this example (115 mg, 0.36 mmol) according to indications of example 5 and example 6 for the cleavage of the benzyl group and the coupling reaction with dopamine hydrochloride. Purification by flash chromatography eluting with 5% MeOH/EtOAc provided the desired product (56 mg, 15%), mp. 205° C. (dec.).
1 H NMR (DMSO-d 6 ): 1.40 (d, J=7.1, 3H); 2.63 (t, J=7.0, 2H); 3.38 (m, 2H); 4.58 (m, 1H); 6.52 (d, J=6.6, 1H); 6.67 (d, J=7.9, 1H); 6.71 (s, 1H); 6.87 (d, J=8.2, 1H); 7.32 (d, J=7.9, 1H); 7.39 (s, 1H); 7.45 (s, 1H), 7.60 (d, J=6.9, 1H); 8.04 (s, 4H).
Example 21
Preparation of N-[′-(p-hydroxybenzoyl)-6-(3-hydroxytyramine)-L-glutamyl]-dopamine
Step A. N-(tert-butoxycarbonyl)-δ-benzyloxy-L-glutamic acid benzyl ester
The title compound was prepared from N-(tert-butoxycarbonyl)-δ-benzyloxy-L-glutamic acid (169 mg, 0.50 mmol) as described in example 2a. Purification by flash chromatography eluting eith 20% EtOAc/hexane provided the title compound as white crystals (186 mg, 87%), mp. 71.5-74° C.
1 H NMR (CDCl 3 ): 1.42 (s, 9H); 1.99 (m, 1H); 2.22 (m, 1H); 2.44 (m, 2H); 4.39 (s, 1H); 5.09 (s, 4H); 7.33 (s, 10H).
Step B. N-(p-hydroxybenzoyl)-δ-benzyloxy-L-glutamic acid benzyl ester
The title compound was prepared from the product obtained in step A of this example (350 mg, 0.80 mmol) by the removal of the Boc group following the indications of example 3. The resulting product was coupled with p-hydroxybenzoic acid according to the indications found in example 4. Purification by flash chromatography eluting with 15% EtOAc/CH 2 Cl 2 provided the desired product as a syrup (161 mg, 43%).
1 H NMR (DMSO-d 6 ): 2.06 (d, J=7.4, 1H); 2.15 (d, J=5.8, 1H); 4.50 (m, 1H); 5.07 (s, 2H); 5.14 (s, 2H); 6.81 (d, J=8.4, 2H); 7.34 (s, 10H); 7.77 (d, J=8.5, 2H); 8.51 (d, J=7.5, 1H); 10.02 (s, 1H).
Step C. N-[′-(p-hydroxybenzoyl)-δ-(3-hydroxytyramine)-L-glutamyl]-dopamine
The title compound was prepared from the compound prepared in step B of this example (116 mg, 0.26 mmol) according to indications found in examples 5 and 6 for the cleavage of the benzyl groups and the coupling reaction with dopamine hydrochloride. Purification by flash chromatography eluting with EtOAc provided the desired product (61.2 mg, 44%), mp. 128° C. (dec.).
1 H NMR (DMSO-d 6 ): 1.89 (m, 1H); 1.98 (m, 1H); 2.14 (t, J=7.6, 2H); 2.50 (t, J=7.7, 4H); 3.17 (m, 4H); 4.33 (m, 1H); 6.39-6.43 (m, 2H); 6.56-6.62 (m, 4H); 6.81 (d, J=8.7, 2H); 7.77 (d, J=8.1, 2H); 7.85 (t, J=5.4, 1H); 7.90 (t, J=5.4, 1H); 8.16 (d, J=7.8, 1H), 8.61 (s, 2H); 8.72 (s, 2H), 9.98 (s, 1H).
Example 22
Preparation of N-[′-(3′,4′-dihydroxybenzoyl)-δ-(3-hydroxytyramine)-L-glutamyl]-dopamine
Step A. N-(3,4-dihydroxybenzoyl)-δ-benzyloxy-L-glutamic acid benzyl ester
The title compound was prepared from N-(tert-butoxycarbonyl)-δ-benzyloxy-L-glutamic acid benzyl ester (350 mg 0.82 mmol) by the removal of the Boc group following the indications found in example 3. The resulting product was coupled with 3,4-dihydroxybenzoic acid according to the indications found in example 4. Purification by flash chromatography eluting with 5% MeOH/EtOAc provided the desired product as a syrup (169 mg, 36%).
1 H NMR (CDCl 3 ): 2.15 (m, 1H); 2.30 (m, 1H); 2.49 (m, 2H); 4.81 (m, 1H); 5.06 (s, 2H); 5.16 (s, 2H); 6.86 (d, J=8.4, 2H); 7.12 ( d, J=7.4, 1H); 7.19 ( d, J=7.4, 1H); 7.26-7.31 (m, 10H); 7.46 (s, 1H).
Step B. N-[N′-(3′,4′-dihydroxybenzoyl)-δ-(3-hydroxytyramine)-L-glutamyl]-dopamine
The title compound was prepared from the compound obtained in step B of this example (130 mg, 0.28 mmol) according to the indications of example 5 and 6 for the removal of the benzyl groups and the coupling with dopamine hydrochloride. Purification by flash chromatography eluting with EtOAc provided the desired product as a foam (23 mg, 15%).
1 H NMR (DMSO-d 6 ): 1.87 (m, 1H,); 1.96 (m, 1H); 2.12 (s, 2H); 2.48 (t, J=7.6, 4H); 3.17 (m, 4H); 4.31 (m, 1H); 6.40 (d, J=7.6, 1H); 6.42 (d, J=7.3, 1H); 6.56 (s, 1H); 6.59 (d, J=8.6, 1H); 6.60 (s, 1H); 6.62 (d, J=7.7, 4H); 6.76 (d, J=8.0, 1H); 7.23 ( d, J=9.6, 1H); 7.32 (s, 1H); 7.85 ( t, J=5.3, 1H); 7.88 ( t, J=5.9, 1H); 8.05 (d, J=7.8, 1H), 8.60 (s, 2H); 8.71 (s, 2H), 9.10 (s, 1H); 9.45 (s, 1H).
Example 23
Preparation of N-[′-(3′,4′-dihydroxybenzoyl)-δ-benzyloxy-L-glutamyl]-dopamine
Step A. N-[N′-(tert-butoxycarbonyl)-δ-benzyloxy-L-glutamyl]-dopamine
The title product was prepared by the reaction of dopamine hydrochloride with N-(tert-butoxycarbonyl)-δ-benzyloxy-L-glutamic acid (500 mg, 1.15 mmol) according to the indications of example 6. Purification by flash chromatography eluting with 25%
EtOAc/CH 2 Cl 2 containing 1% acetic acid provided the desired product (400 mg, 65%) as a solid, mp. 58° C.
1 H NMR (acetone-d 6 ): 1.40 (s, 9H,); 1.95 (m, 1H); 2.14 (m, 1H); 2.46 (t, J=7.3, 4H); 2.65 (t, J=7.0, 2H), 3.38 (m, 2H); 4.19 (m, 1 H); 5.1 1 (s, 2H), 6.19 (d, J=7.4, 1H); 6.55 (d, J=8.2, 1H); 6.74 (m, 2H); 7.29-7.33 (m, 5H), 7.43 (m, 1H), 7.75 (br s, 1H), 7.83 (br s, 1H).
Step B. N-[N′-(3′,4′-dihydroxybenzoyl)-δ-benzyloxy-L-glutamyl]-dopamine
The title compound was prepared from the product of step A of this example (400 mg, 0.84 mmol) by the removal of the Boc group following the indications of example 3. The resulting compound was then coupled with 3,4-dihydroxybenzoic acid according to indications found in example 4. Purification by flash chromatography eluting with EtOAc containing 1% acetic acid provided the desired product (124 mg, 28%) as a solid, mp 108° C.
1 H NMR (acetone-d 6 ): 2.02 (m, 1H), 2.23 (m, 1H), 2.47 (m, 1H,); 2.50 (t, J=7.0, 2H); 3.35 (m, 2H); 4.61 (m, 1H); 5.05 (s, 2H), 6.48 (d, J=7.6, 1H); 6.64 (d, J=7.6, 1H); 6.68 (s, 1H); 6.82 (d, J=8.8, 1H); 6.90-7.03 (m, 1H); 7.25-7.31 (m, 5H), 7.44 (s, 1H), 7.49 (m, 1H), 7.66 (d, J=7.8, 1H); 7.5-8.8 (br s, 4H)
Example 24
Preparation of N-[′-(3′,4′-dihydroxybenzoyl)-L-glutaminyl]-dopamine
Step A. N-(tert-butoxycarbonyl)-L-glutamine benzyl ester
The title compound was prepared from N-(tert-butoxycarbonyl)-L-glutamine (250 mg, 1.0 mmol) as described in example 2b. Purification by flash chromatography eluting with 5% MeOH/EtOAc provided the desired product as crystals (320 mg, 96%), mp. 105.5-107.5° C.
1 H NMR (CDCl 3 ): 1.43 (s, 9H); 1.94 (m, 1 H); 2.19 (m, 1H); 2.27 (m, 1H); 4.36 (s, 1H); 5.15 (m, 2H); 5.37 (d, J=7.3, 1H); 5.58 (s, 1H); 7.35 (m, 5H).
Step B. N-(3,4-dihydroxybenzoyl)-L-glutamine benzyl ester
The title compound was prepared from the product of step A of this example (300 mg, 0.89 mmol) by the removal of the Boc group following the indications of example 3. The resulting compound was then coupled with 3,4-dihydroxybenzoic acid according to indications found in example 4. Purification by flash chromatography eluting with 5% MeOH/EtOAc provided the desired product as a syrup (154 mg, 46%).
1 H NMR (DMSO-d 6 ): 1.96 (m, 1H); 2.06 (m, 1H); 2.21 (m, 2H); 4.40 (m, 1H); 5.13 (s, 2H); 6.78 (d, J=8.4, 1H); 6.82 (s, 1H); 7.24 ( d, J=7.6, 1H); 7.31 ( s, 2H); 7.33-7.36 (m, 5H,); 8.52 (d, J=6.9, 1H); 9.12 (s, 1H); 9.49 (s, 1H)
Step C. N-[N′-(3′,4′-dihydroxybenzoyl)-L-glutamine]-dopamine
The title compound was prepared from the compound obtained in step B of this example (110 mg, 0.3 mmol) according to the indications found in example 5 and example 6 for the removal of the benzyl group and the coupling with dopamine hydrochloride. Purification by flash chromatography eluting with 7.5% MeOH/EtOAc provided the desired product as a solid (24.5 mg, 20%), mp. 164° C. (dec.).
1 H NMR (DMSO-d 6 ): 1.85 m, 1H); 1.95 m, 1H); 2.13 (s, 2H); 2.51 (s, 2H); 3.18 (m, 2H); 4.30 (m, 1H); 6.41 (d, J=7.9, 1H); 6.59 (d, J=7.8, 1H); 6.58 (s, 1H); 6.77 (d, J =8.5, 1H); 7.24 (d, J=8.7, 1H); 7.29 (s, 1H); 7.31 (s, 2H); 7.89 (t, J=5.3, 1H); 8.12 (d, J=7.6, 1H), 8.61 (s, 1H); 8.72 (s, 1H), 9.19 (s, 1H); 9.46 (s, 1H).
Example 25
Preparation of N-[N′-(p-hydroxybenzoyl)-L-leucyl]-dopamine
Step A. N-(p-hydroxybenzoyl)-L-leucine methyl ester
The title compound was prepared from L-leucine methyl ester hydrochloride (182 mg, 1.0 mmol) as described in example 4. Purification by flash chromatography eluting with 5% MeOH/CHCl 3 provided the desired product as white crystals (138 mg, 52%), mp. 138-140° C.
1 H NMR (DMSO-d 6 ): 0.88 (d, J=6.5, 3H); 0.93 (d, J=6.6, 3H); 1.55 (m, 1H); 1.68 (m, 1H); 1.75 (m, 1H); 3.36 (s, 3H); 4.47 (m, 1H); 6.82 (d, J=8.3, 2H); 7.77 (d, J=8.3, 2H); 8.42 (d, J=7.7, 1H); 9.99 (s, 1H).
Step B. N-[N′-(p-hydroxybenzoyl)-L-leucyl]-dopamine
The title compound was prepared from the compound obtained in step A of this example (96 mg, 0.40 mmol) by saponification of the methyl ester group according to example 8. The resulting acid was coupled with dopamine hydrochloride as in example 6. Flash chromatography eluting with 100% EtOAc provided the title compound (96 mg, 63%), mp. 161° C. (dec.).
1 H NMR (DMSO-d 6 ): 0.84 (d, J=5.5, 3H); 0.90 (d, J=6.6, 3H); 1.47 (m, 1H); 1.60 (m, 2H); 2.52 (m, 2H); 3.17 (m, 2H); 4.43 (m, 1H); 6.42 (d, J=8.0, 1H); 6.58 (d, J=6.1, 1H); 6.60 (s, 1H); 6.81 (d, J=9.1, 2H); 7.78 (d, J=8.4, 2H); 7.88 (t, J=5.5, 1H); 8.09 (d, J=8.5, 1H); 8.61 (s, 1H); 8.69 (s, 1H); 9.95 (s, 1H).
Example 26
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-leucyl]-dopamine
Step A. N-[N′(tert-butoxycarbonyl)-L-leucyl]-dopamine
The title compound was prepared from N-(tert-butoxycarbonyl)-L-leucine (187 mg, 0.75 mmol) by coupling with dopamine hydrochloride as in example 6. Flash column chromatography eluting with 25% EtOAc/CH 2 Cl 2 provided the title compound as a syrup (195 mg, 71%).
1 H NMR (CDCl 3 ): 0.88 (t, J=6.5, 6H); 1.42 (s, 9H); 1.59 (s, 2H); 2.64 (t, J=6.7, 2H); 3.44 (m, 2H); 4.13 (s, 1H); 5.21 (s, 1H); 6.54 (d, J=7.9, 1H); 6.66 (s, 1H); 6.61 (s, 1H); 6.78 (d, J=7.7, 1H).
Step B. N-[N′-(3′,4′-dihydroxybenzoyl)-L-leucyl]-dopamine
The title compound was prepared from the product obtained in step A of this example (176 mg, 0.48 mmol) by removing the Boc group following the indications of example 3. The resulting unblocked product was coupled with 3,4-dihydroxybenzoic acid according to example 4. Purification by flash chromatography eluting with 5% MeOH/EtOAc provided the desired product (42 mg, 22%), mp. 132° C. (dec.),
1 H NMR (DMSO-d 6 ): 0.85 (d, J=5.6, 3H); 0.89 (d, J=5.2, 3H); 1.45 (m, 1H); 1.60 (m, 2H); 2.50 (t, J=7.2, 2H); 3.19 (m, 2H); 4.40 (m, 1H); 6.41 (d, J=7.8, 1H); 6.57 (s, 1H); 6.59 (d, J=7.6, 1H); 6.75 (d, J=7.5, 1H); 7.24 (d, J=10, 1H); 7.31 (s, 1H); 7.86 (t, J=5.5, 1H); 7.86 (d, J=7.8, 1H); 8.66 (s, 1H); 9.08 (s, 1H); 9.42 (s, 1H).
Example 27
Preparation of N-[N′-(p-hydroxybenzoyl)-L-prolyl]-dopamine
Step A. N-[N′-(tert-butoxycarbonyl)-L-prolyl]-dopamine
The title compound was prepared from N-(tert-butoxycarbonyl)-L-proline (108 mg, 0.50 mmol) in a coupling reaction with dopamine hydrochloride (189 mg, 1.0 mmol) according to example 6. Purification by flash column chromatography (5% MeOH/CHCl 3 ) provided the desired compound as a syrup (128 mg, 73%).
1 H NMR (DMSO-d 6 ): 1.32 (s, 6H); 1.39 (s, 3H,); 1.72 (m, 2H); 1.76 (m, 1H); 2.06 (m, 1H); 2.50 (s 2H); 3.13 (m, 1H); 3.25 (m, 2H); 3.27 (m, 1H); 3.98 (m, 1H); 6.43 (d, J=7.4, 1H); 6.56 (s, 1H); 6.61 (d, J=7.9, 1H); 7.86 (s, 1H); 8.31 (s, 1H); 8.61 (s, 1H); 8.71 (s, 1H).
Step B. N-[N′-(p-hydroxybenzoyl)-L-prolyl]-dopamine
The title compound was prepared from the product obtained in step A of this example by the removal of the Boc group following the indications found in example 3. The resulting unblocked derivative was then coupled with p-hydroxybenzoic acid according to the indications found in example 4. Purification by flash chromatography eluting with EtOAc afforded the desired product (23 mg, 31%), mp. 165° C. (dec.).
1 H NMR (DMSO-d 6 ): 1.74 (m, 2H); 1.85 (s, 1H); 2.10 (s, 1H); 2.50 (s 2H); 3.17 (s, 2H); 3.46 (s, 1H); 3.57 (s, 1H); 4.09 (s, 1H); 6.43 (d, J=6.8, 1H); 6.58 (s, 1H); 6.61 (d, J=7.9, 1H); 6.78 (d, J=7.2, 2H); 7.43 (d, J=7.0, 2H); 7.83 (s, 1H); 8.63 (s, 1H); 8.73 (s, 1H); 9.88 (s, 1H).
Example 28
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-prolyl]-dopamine
The title compound was prepared from N-(tert-butoxycarbonyl)-L-prolyl-dopamine (150 mg, 0.43 mmol) by the removal of the Boc group following the indications found in example 3. The resulting unblocked derivative was then coupled with 3,4-dihydroxybenzoic acid as in example 4. Purification by flash chromatography eluting with EtOAc afforded the desired product (54 mg, 32%) as a solid, mp. 131° C. (dec.).
1 H NMR (DMSO-d 6 ): 1.73 (s, 2H); 1.85 (s, 1H); 2.09 (s, 1H); 2.50 (s 2H); 3.17 (s, 2H); 3.48 (s, 1H); 3.56 (s, 1H); 4.09 (s, 1H); 6.43 (d, J=6.7, 1H); 6.58 (s, 1H); 6.61 (d, J=78.4, 1H); 6.76 (d, J=7.3, 1H); 6.90 (s, 1H); 7.00 (s, 1H); 7.84 (s, 1H); 8.62 (s, 1H); 8.72 (s, 1H); 9.13 (s, 1H); 9.33 (s, 1H).
Example 29
Preparation of N-[N′-(p-hydroxybenzoyl)-L-tryptophanyl]-dopamine
Step A. N-[N′-(tert-butoxycarbonyl)-L-tryptophanyl]-dopamine
The title compound was prepared from N-(tert-butoxycarbonyl)-L-tryptophan (204 mg, 0.65 mmol) by coupling with dopamine hydrochloride according to the procedure of example 6. Purification by flash chromatography eluting with 2.5% MeOH/EtOAc provided the title compound as a syrup (215 mg, 75%).
1 H NMR (DMSO-d 6 ): 1.31 (s, 9H); 2.46 (t, J=7.4, 2H); 3.02 (m, 2H); 3.14 (m, 1H); 3.22(s, 1H); 4.15 (m, 1H); 6.43 (d, J=7.6, 1H); 6.58 (s, 1H); 6.62 (d, J=7.5, 1H); 6.66 (d, J=8.1, 1H); 6.97 (t, J=7.5, 1H); 7.05 (t, J=7.3, 1H); 7.10 (s, 1H); 7.31 (d, J=7.7, 1H); 7.58 (d, J=7.7, 1H); 7.86 (t, J=4.7, 1H); 8.62 (s, 1H); 8.71 (s, 1H); 10.77 (s, 1H).
Step B. N-[N′-(p-hydroxybenzoyl)-L-tryptophanyl]-dopamine
The title compound was prepared from the product obtained in step A of this example (175 mg, 0.40 mmol) by removing the Boc group following the indications of example 3. The resulting unblocked derivative was then coupled with p-hydroxybenzoic acid according to the indications of example 4. Purification by flash chromatography eluting with 5% MeOH/EtOAc afforded the desired product (125 mg, 68%) as a foam.
1 H NMR (DMSO-d 6 ): 2.50 (t, J=7.6, 2H); 3.11(m, 1H, CH 2(2) ); 3.18 (m, 2H) 3.24 (m, 1H); 4.65 (m, 1H); 6.43 (d, J=8.1, 1H); 6.59 (s, 1H,); 6.61 (d, J=8.1, 1H); 6.76 (d, J=8.6, 2H); 6.98 (t, J=7.4, 1H); 7.05 (t,J=7.6, 1H); 7.17 (s, 1H); 7.30(d, J=8.1, 1H); 7.65 (d, J=8.0, 1H); 7.67 (d, J=8.3, 2H); 8.03 (t, J=5.3, 1H); 8.12 (d, J=8.2, 1H); 8.69 (s, 2H); 9.95 (s, 1H); 10.74 (s, 1H).
Example 30
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-tryptophyl]-dopamine
The title compound was prepared from N-[(N′-(tert-butoxycarbonyl)-L-tryptophyl]-dopamine (44 mg, 0.10 mmol) by the removal of the Boc group following the indications of example 3. The resulting unblocked derivative was then coupled with 3,4-dihydroxybenzoic acid according to the conditions found in example 4. Purification by flash chromatography eluting with EtOAc afforded the desired product (25 mg, 53%) as a yellow solid, mp. 119° C. (dec.)
1 H NMR (DMSO-d 6 ): 2.47 (m, 2H); 3.13 (m, 1H); 3.17 (m, 2H); 3.22 (m, 1H,); 4.62 (m, 1H); 6.43 (d, J=7.4, 1H); 6.59 (s, 1H); 6.61 (d, J=7.9, 1H); 6.73 (d, J=8.0, 1H); 6.97 (t, J=7.7, 1H); 7.04 (t, J=7.3, 1H); 7.15 (s, 1H); 7.29 (d, J=8.1, 1H); 7.24 (s, 1H); 7.29 (d, J=6.1, 1H); 7.64 (d, J=8.0, 1H); 7.66 (t, J=6.6, 1H); 8.00 (d, J=7.00, 1H); 8.61 (s, 1H); 8.72 (s, 1H); 9.07 (s, 1H); 9.44 (s, 1H); 10.74 (s, 1H);.
Example 31
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-methionyl]-dopamine
Step A. N-[N′-(tert-butoxycarbonyl)-L-methionyl]-dopamine
The title compound was prepared from N-(tert-butoxycarbonyl)-L-methionine (250 mg, 1.0 mmol) by coupling with dopamine (380 mg, 2.0 mmol) according to example 6. Purification by flash chromatography eluting with 30% EtOAc/CH 2 Cl 2 yielded the title compound (230 mg, 60%).
1 H NMR (DMSO-d 6 ): 1.38 (s, 9H); 1.73 (m, 1H); 1.80 (m, 1H); 2.02 (s, 3H); 2.40 (m, 2H); 2.51 (t, J=7.6, 2H); 3.24 (m, 2H); 3.96 (m, 1H); 6.43 (d, J=7.6, 1H,); 6.57 (s, 1H); 6.61 (d, J=8.4, 1H); 6.87 (d, J=7.9, 1H); 7.78 (t, J=5.0, 1H); 8.62 (s, 1H); 8.70 (s, 1H).
Step B. N-[N′-(3′,4′-dihydroxybenzoyl)-L-methionine]-dopamine
The title compound was prepared from the product prepared in step A of this example (150 mg, 0.40 mmol) by the removal of the Boc group following the indications found in example 3. The resulting unblocked derivative was coupled with 3,4-dihydroxybenzoic acid according to the indications of example 4. Purification by flash chromatography eluting with 5% MeOH/EtOAc afforded the desired product (40 mg, 24%) as a solid, mp. 126° C. (dec.).
1 H NMR (DMSO-d 6 ): 1.93 (m, 2H); 2.05 (s, 3H); 2.42 (m, 1H); 2.47 (m, 1H); 2.53 (t, J=7.8, 2H); 3.17 (m, 2H); 4.43 (m, 1H); 6.43 (d, J=8.0, 1H); 6.57 (s, 1H,); 6.59 (d, J=8.0, 1H); 6.77 (d, J=8.1, 1H); 7.25 (d, J 8.1, 1H); 7.32 (s, 1H); 7.89 (t, J=5.6, 1H); 8.08 (d, J=7.9, 1H); 8.67 (s, 4H).
Example 32
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-lysyl]-dopamine
Step A. N-[N α ′-(9-fluorenylmethoxycarbonyl)-N ε ″-(tert-butoxycarbonyl)-L-lysyl]-dopamine
The title compound was prepared from N α -(9-fluorenylmethoxycarbonyl)-N ε ′-(tert-butoxycarbonyl)-L-lysine (230 mg, 0.50 mmol) by coupling with dopamine hydrochloride as described in example 6. Purification by flash chromatography eluting with 40% EtOAc/CH 2 Cl 2 provided the desired product as white crystals, mp. 58-61° C. (280 mg, 93%).
1 H NMR(DMSO-d 6 ): 1.20 (m, 1H); 1.23 (m, 1H); 1.33 (m, 2H); 1.48 (m, 1H); 1.55 (m, 1H); 2.52 (m, 2H); 2.89 (s, 2H); 3.15 (m, 1H); 3.22 (m, 1H); 3.89 (q, J NH =8.5, J=6.8, 1H); 4.21 (t, J=6.1, 1H); 4.22 (d, J=7.4, 2H); 6.43 (d, J=7.9, 1H); 6.75 (s, 1H); 6.61 (d, J=7.6, 1H); 6.74 (s, 1H); 7.37 (d, J=8.0, 1H); 7.32 (t, J=7.4, 2H,); 7.42 (t, J=7.4, 2H); 7.72 (, J=6.6, 2H); 7.86 (t, J=5.7, 1H); 7.88 (d, J=7.5, 2H); 8.62 (br s, 1H); 8.71 (br s, 1H).
Step B. N-[′-(3′,4′-dihydroxybenzoyl)-L-lysyl]-dopamine
The title compound was prepared from the compound prepared in step A of this example (140 mg, 0.23 mmol) by the removal of the Fmoc group following the indications found in example 7. The resulting unblocked derivative was coupled with 3,4-dihydroxybenzoic acid according to the indications of example 4. Purification by flash chromatography using EtOAc provided the desired product (85 mg, 41%). The cleaving of the Boc group of the side chain of the coupled product (20 mg, 0.04 mmol) was achieved via an acid hydrolysis as described in example 3. The solvent and acid were removed under vacuum to afford the desired product (14.4 mg, 86%), mp.93.5° C. (dec.).
1 H NMR(DMSO-d 6 ): 1.17 (m, 2H); 1.52 (m, 2H); 1.68 (m, 2H,; 2.53 (m, 2H); 2.76 (s, 2H); 3.18 (m, 2H), 4.34 (q, J=6.7, J=8.2, 1H); 6.43 (d, J=8.0, 1H); 6.57 (s, 1H); 6.61 (d, J=8.0, 1H); 6.78 (d, J=8.2, 1H); 7.24 (d, J=8.2, 1H); 7.33 (s, 1H); 7.91 (t, J=4.7, 1H); 7.97 (d, J=7.9, 1H); 8.68 (s, 4H).
Example 33
Preparation of N-[N′-3′,4′-dihydroxybenzoyl)-L-histidyl]-dopamine
Step A. N-[N α ′-(fluorenylmethoxycarbonyl)-N″ im -(trityl)-L-histidyl]-dopamine
The title compound was prepared from N α -(fluorenylmethoxycarbonyl)-N″ im -trityl-histidine (619 mg, 1.0 mmol) according to the indications found in example 6 with dopamine hydrochloride. Purification by flash chromatography eluting with 40% EtOAc/CH 2 Cl 2 provided the desired product (390 mg, 52% yield).
1 H NMR(DMSO-d 6 ): 3.16 (m, 1H); 4.14 (m, 1H); 4.18 (d, J=7.4, 2H); 4.20 (t, J=5.4, 1H); 6.39 (d, J=7.6, 1H); 6.56 (s, 1H); 6.60 (d, J=7.8, 1H); 7.03 (s, 6H); 7.07 (t, J=7.4, 1H); 7.23 (s, 1H); 7.27 (m, 2H); 7.31 (s, 9H); 7.40 (m, 2H); 7.68 (m, 2H); 7.85 (d, J=7.8, 1H); 7.90 (d, J=7.7, 2H); 7.95 (s, 1H); 8.63 (br s, 1H); 8.72 (br s, 1H).
Step B. N-[N′-(3′,4′-dihydroxybenzoyl)-L-histidyl]-dopamine
The title compound was prepared from the compound prepared in step A of this example (320 mg, 0.42 mmol) by the removal of the Fmoc group as described in example 7. The resulting unblocked derivative was coupled with 3,4-dihydroxybenzoic acid as in example 4. Purification by flash chromatography eluting with 5% MeOH/EtOAc provided the desired compound (85 mg, 41%). For the removal of the trityl group located on the side chain, the product (60 mg, 0.089 mmol) was hydrogenolyzed following the conditions found in example 5 affording the desired product (30 mg, 79%).
1 H NMR(DMSO-d 6 ): 2.47 (t, J=7.6, 2H); 2.96 (m, 2H); 3.17 (m, 2H); 4.57 (q, J=7.8, J NH =6.7, 1H); 6.41 (d, J=9.1, 1H); 6.57 (s, 1H); 6.60 (d, J=8.2, 1H); 6.78 (d, J=8.4, 1H); 6.87 (s, 1H); 7.20 (d, J=7.8, 1H); 7.28 (s, 1H); 7.78 (s, 1H); 7.88 (t, J=5.7, 1H); 8.23 (d, J=7.9, 1H); 8.65 (s, 2H); 9.15 (s, 1H). 9.55 (s, 1H).
Example 34
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-aspartyl]-dopamine
Step A. N-tert-butoxycarbonyl-γ-cyclohexyl-L-aspartic acid benzyl ester
The title compound was prepared from N-tert-butoxycarbonyl-L-aspartic acid γ-cyclohexyl ester (1.0 g, 3.2 mmol) by an alkylation with benzyl bromide following the indication of example 2c. The resulting ester was obtained in 98% yield after purification by flash chromatography eluting with 15% EtOAc/hexane.
Step B. N-(3,4-dihydroxybenzoyl)-γ-cyclohexyloxy-L-aspartic acid benzyl ester
The title compound was prepared from the compound prepared in step A of this example by the removal of the Boc group according to the indications found in example 3 and coupling with 3,4-dihydroxybenzoic acid as indicated in example 4. Purification by flash chromatography eluting with 20% ethyl acetate/CH 2 Cl 2 provided the title compound (260 mg, 52%).
Step C. N-[N′-(3′,4′-dihydroxybenzoyl)-γ-cyclohexyloxy-L-aspartyl]-dopamine
The title compound was prepared from the compound prepared in step B of this example (259 mg, 0.59 mmol) by hydrogenolysis of the benzyl ester following the conditions outlined in example 5. The resulting product was then subjected to coupling with dopamine hydrochloride according to example 6. Purification by flash chromatography eluting with ethyl acetate afforded the title compound in 49% yield.
Example 35
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-sarcosyl]-dopamine
Step A. N-tert-butoxycarbonyl-sarcosine benzyl ester
The title compound was prepared from N-tert-butoxycarbonyl-sarcosine (2.0 g, 10.6 mmol) by an alkylation with benzyl bromide following the indication of example 2c. The resulting ester (2.89 g; 98%) was obtained after purification by flash chromatography eluting with 15% EtOAc/hexane.
1 H NMR (CDCl 3 ): 1.43 (d, 9H), 2.94 (d, 3H), 3.97 (d, 2H), 7.36 (s, 5H)
Step B. N′-(3,4-dihydroxybenzoyl)-sarcosine benzyl ester
The title compound was prepared from the compound prepared in step A of this example by the removal of the Boc group according to the indications found in example 3 and coupling with 3,4-dihydroxybenzoic acid as indicated in example 4. Purification by flash chromatography eluting with 80% ethyl acetate/CH 2 Cl 2 provided the title compound (433 mg, 43%).
1 H NMR (CDCl 3 ): 3.1 (d, 3H), 3.5 (s, 2H), 5.2 (d, 2H), 6.9 (m, 3H), 7.40 (m, 5H), 9.40 (br s, 2H).
Step C. N-[N′-(3′,4′-dihydroxybenzoyl)-sarcosinyl]-dopamine
The title compound was prepared from the compound prepared in step B of this example (278 mg, 0.88 mmol) by hydrogenolysis of the benzyl ester following the conditions outlined in example 5. The resulting product was then subjected to coupling with dopamine hydrochloride according to example 6. Purification by flash chromatography eluting with 5% MeOH/CH 2 Cl 2 /1% AcOH afforded the title compound in 50% yield.
1 H NMR (CDCl 3 ): 2.60 (t, 2H), 2.9 (d, 3H), 3.2 (q, 2H), 3.3 (t, 2H), 6.4-7.0 (m, 6H), 9.5 (br s, 4H).
Example 36
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-tyrosyl]-L-tyrosine
The dipeptide was prepared using the peptide synthesizer (ABI 430A) utilising Wang resin (0.5 mmol).
Step A. H 2 N-L-tyrosyl-L-tyrosyl-resin
The N-Fmoc-L-tyrosine(t-Bu)-OH (1 mmol was activated over a period of 45 min with HOBT (1.0 eq.) and DCC (1.0 eq.) in 5 mL of N-methylpyrrolidone (NMP). At the same time, in a separate flask, the Fmoc protecting group on the tyrosine amino group bound to the polymer was removed by two successive treatments of 15 min with a solution of 30% piperidine in N-methylpyrrolidone, followed by a series of washes with NMP. The activated ester was then filtered and added to the resin. The suspension was stirred for 2 h. The Fmoc blocking group was then removed as previously described and the resin was successively washed with N-methylpyrrolidone and CH 2 Cl 2 .
Step B. N-[N′-(3′,4′-dihydroxybenzoyl)-L-tyrosyl]-L-tyrosyl-resin
To the dityrosyl moiety bound on the resin (1 g) and 3,4-dihydroxybenzoic acid (85 mg; app. 3 eq.) in DMF (5 mL) and CH 2 Cl 2 (2 mL) were added BOP (benzotriazol-1-yloxy-tris-dimethylamino)phosphonium hexafluorophosphate) (240 mg, app. 3 eq.) and diisopropylethylamine (125 μL; 4 eq.). The flask was stirred under nitrogen for a period of 16 h. The resin was filtered off, washed successively with DMF, MeOH and CH 2 Cl 2 , yielding 518 mg of crude resin.
Step C. N-[N′-(3′,4′-dihydroxybenzoyl)-L-tyrosyl]-L-tyrosine
A mixture of 0.5 mL water in 4.5 mL of trifluoroacetic acid was cooled to 0° C. and was added to the crude resin. The resulting suspension was stirred, allowing the mixture to reach room temperature over a period of 2 h. The mixture was then filtered and the resin washed with 5 mL of acetic acid. The filtrate was evaporated to dryness in vacuo and the residue was purified by preparative HPCL, using a Supelcosil C-18 column, flow rate: 18 mL/min; gradient: 0.1% TFA from 0-30% acetonitrile over 40 min. Retention time: 21 min. 5 mg (4%) of the title compound was recovered (4% yield).
Example 37
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-tyrosyl]-glycine
Step A. N-(3,4-dihydroxybenzoyl)-O-tert-butyltyrosine tert-butyl ester
The hydrochloric salt of L-O-tert-butyltyrosine tert-butyl ester (800 mg, 2.4 mmol) was coupled with 3,4-dihydroxybenzoic acid by following the directions found in example 9. Purification by flash chromatography eluting with 40% ethyl acetate in hexane afforded the desired product (385 mg, 37%).
1 H NMR (CDCl 3 ): 1.31 (s, 9H), 1.42 (s, 9H), 3.13 (dd, J=5.8, 14.3, 1H), 3.17 (dd, J=6.3, 14.3, 1H), 4.85 (ddd, J=5.8, 6.3, 4.0, 1H), 6.77 (d, J=7.4, 1H), 6.5-6.9 (br s, 0.5H) and 7.26 (s, 0.5H), 6.80 (d, J=8.2,), 6.91 (d, J=8.0, 2H,), 7.03 (d, J=8.2, 1H), 7.08 (d, J=8.0, 2H), 7.54 (s, 1H), 7.8-8.4 (br s, 1H).
Step B. N-[N′-(3′,4′-dihydroxybenzoyl)-L-O-tert-butyltyrosyl]-glycine
The product of step A of this example (375 mg) was stirred with TFA (10 mL) for a period of 90 min. The mixture was evaporated to dryness in vacuo and several h with a mechanical pump providing a quantitative yield (200 mg) of the free acid. The acid was then condensed using the BOP procedure as found in example 9 with glycine tert-butyl ester hydrochloride salt (80 mg,1.5 eq.) and triethylamine (132 μL, 3.0 eq.) for a period of 15 h. Purification by flash chromatography eluting with 80% EtOAc in hexane afforded the desired product (120 mg, 89%) as the tert-butyl ester. The ester was hydrolysed using 0.5 mL of water and 7 mL of TFA with stirring for 1 h. The mixture was then evaporated in vacuo and purified by flash chromatography eluting with 5% methanol in dichloromethane containing 1% acetic acid to provide the desired product (35 mg, 34%).
1 H NMR (DMSO-d 6 ): 2.86 (dd, J=10.8, 13.7,1H), 2.98 (dd, J=1.4, 13.7, 1H), 3.66-3.92 (m, 2H), 6.61 (d, J 8.2, 2H), 6.73 (d, J 8.4, 1H), 7.09 (d, J8.2, 1H), 7.16 (d, J 8.4, 1H), 7.23 (s, 1H), 8.09 (d, J=8.5, 1H), 8.26 and 8.38 (2t, J=5.6, 2×0.5H).
Example 38
N-[N′-[N″-(3″,4″-dihydroxybenzoyl)-L-tyrosyl]-glycyl]-dopamine
Step A. N-Boc-glycyl-dopamine
The title compound was prepared by coupling dopamine hydrochloride with tert-butoxycarbonylglycine (200 mg, 1.1 mmol) according to the procedure of example 9. Purification by flash chromatography afforded the title compound (214 mg, 64%).
1 H NMR (DMSO-d 6 ): 1.38 (s, 9H), 2.5-2.58 (m, 2H), 3.16-3.20 (m, 2H), 3.49 (d, J=5.7, 2H), 6.42 (d, J=7.9, 1H), 6.57 (s, 1H), 6.62 (d, J=7.9), 6.86 (d, J=5.2, 1H), 7.71-7.77 (m, 1H), 8.62 (s, 1H), 8.72 (s, 1H).
Step B. N-[N′-[N″-(3″,4″-dihydroxybenzoyl)-L-tyrosyl]-glycyl]-dopamine
The product obtained in step A of this example was hydrolyzed under the conditions of example 3 providing an intermediate that was coupled with N-(3,4-dihydroxybenzoyl)-L-tyrosine under the conditions outlined in example 9. Purification by flash chromatography eluting with 5% methanol in ethyl acetate containing 1% acetic acid provided the title compound (30 mg, 19%).
1 H NMR (DMSO-d 6 ): 2.52 (t, J=7.8, 2H), 2.88 (dd, J=9.9, 13.8, 1H), 2.97 (dd, J=4.3, 13.8, 1H), 3.16-3.21 (m, 2H), 3.61 (dd, J=5.2, 16.5, 1H), 3.70 (dd, J=5.6, 16.5, 1H), 4.46-4.53 (m, 1H), 6.44 (dd, J=1.5, 8.2, 1H), 6.56 (d, J=1.5, 1H), 6.62 (d, J=8.2, 1H), 6.63 (d, J=8.5, 2H), 6.74 (d, J=7.9, 1H), 7.09 (d, J=8.5, 2H), 7.18 (dd, J=1.7, 7.9, 1H), 7.25 (d, J=1.7, 1H), 7.76 (t, J=5.4, 1H), 8.19-8.23 (m, 2H), 8.1-9.7 (br s, 5H).
Example 39
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-glycyl]-L-tyrosine
Step A. N-3,4-dihydroxybenzoyl-glycine
Coupling of the hydrochloride salt of glycine tert-butyl ester with 3,4-dihydroxybenzoic acid was obtained by following the indications of example 9. Purification by flash chromatography afforded 288 mg (81%) of the title compound after eluting with 4% methanol in methylene chloride.
1 H NMR (DMSO-d 6 ): 1.41 (s, 9H), 3.82 (d, J 5.6, 2H), 6.76 (d, J=8.0, 1H), 7.20 (d, J=8.0, 1H), 7.28 (s, 1H), 8.45 (t, J=5.6, 1H),9.13 (s, 1H), 9.47 (s, 1H).
Step B. N-[N′-(3′,4′-dihydroxybenzoyl)-glycyl]-L-tyrosine
The product obtained in step A of this example was hydrolyzed by stirring in TFA (10 mL) for a period of 90 min. Evaporation of the acid in vacuo afforded a product that was then reacted with O-tert-butyl-L-tyrosyl-dopamine using the conditions outlined in example 9. Purification by flash chromatography eluting with 70% ethyl acetate in hexane provided 230 mg (67%) of the O-tert-butyl derivative of the title compound.
1 H NMR (CDCl 3 ) d 1.28 (s, 9H), 1.30 (s, 9H), 3.00 (d, J=5.4, 2H), 3.89-4.08 (m, 2H), 4.60-4.67 (m, 1H), 6.64 (d, J=7.3, 1H), 6.83 (d, J=8.0, 2H), 6.97-7.05 (m, 1H), 7.04 (d, J=8.1, 2H), 7.09-7.18 (m, 2H), 7.32-7.41 (m, 1H).
Treatment of the tert-butyl derivative with TFA for a period of 2 h provided a quantitative yield of the title product.
1 H NMR (DMSO-d 6 ): 2.75-2.93 (m, 2H), 3.73-3.87 (m, 2H), 4.35-4.44 (m, 1H), 6.62 (d, J=8.1, 2H), 6.76 (d, J=8.5, 1H), 6.98 (d, J=8.1, 2H), 7.20 (dd, J=1.6, J=8.5, 1H), 7.30 (d, J=1.6, 1H), 7.96 (d, J=8.1, 0.5H) 8.18 (d, J=7.7, 0.5H), 8.29-8.36 (m, 1H), 9.00-9.60 (br s, 4H).
Example 40
N-[-N′-[N″-(3″,4″-dihydroxybenzoyl)-glycyl]-L-tyrosyl]-dopamine
Step A. N-L-tyrosine-dopamine
The title compound was prepared from N-tert-butoxycarbonyl-O-2,6-dichlorobenzyl-L-tyrosine (2.50 g, 5.7 mmol) according to the indications found in example 6 with dopamine hydrochloride. Purification by flash chromatography eluting with 50% EtOAc/hexane provided the desired product (3.03 g, 93%).
1 H NMR (DMSO-d 6 ): 1.31 (s, 9H), 2.45-2.55 (m, 2H), 2.67 (dd, J=10.2, 13.4, 1H), 2.86 (dd, J=4.1, 13.4, 1H), 3.10-3.18 and 3.20-3.29 (2m, 2H), 4.07 (ddd, J=4.1, 10.2, 8.5, 1H), 5.17 (s, 2H), 6.43 (d, J=7.8, 1H), 6.59 (s, 1H), 6.64 (d, J=7.8, 1H), 6.75 (d, J=8.5, 1H), 6.94 (d, J=8.2, 2H), 7.15 (d, J=8.2, 2H), 7.45 (t, J=8.1, 1H), 7.53 (d, J=8.1, 2H), 7.87 (t, J=4.9, 1H), 8.00-9.15 (br s, 2H).
Step B. N-[N′-[N″-(3″,4″-dihydroxybenzoyl)-glycyl]-L-tyrosyl]-dopamine
The product obtained in step A of this example was hydrolyzed by stirring in TFA (10 mL) for a period of 30 min. Evaporation of the acid in vacuo afforded a product, part of which (148 mg, 0.70 mmol) was then reacted with N-3,4-dihydroxybenzoyl-glycine using the conditions outlined in example 9. Purification by flash chromatography eluting with 5% methanol in ethyl acetate provided 115 mg (25%) of the O-(2,6-dichlorobenzyl derivative of the title compound. The latter protected dipeptide derivative (115 mg, 0.17 mmol) in 4 mL of methanol was then hydrogenolyzed according to the procedure found in example 5. Purification by flash chromatography eluting with 2% methanol in ethyl acetate provided 60 mg (68%) of the desired product.
1 H NMR (DMSO-d 6 ): 2.47 (t, J=7.7, 2H), 2.65 (dd, J=8.9, J=13.6, 1H), 2.83 (dd, J=4.7, 13.6, 1H), 3.08-3.23 (m, 2H), 3.71 (dd, J=5.6, J=16.2, 1H), 3.83 (dd, J=5.8, 16.2, 1H), 4.35 (ddd, J=4.7, 8.9, 8.4, 1H), 6.42 (d, J=7.7, 1H), 6.57 (s, 1H), 6.59 (d, J=8.3, 2H), 6.62 (d, J=7.7, 1H), 6.76 (d, J=8.0, 1H), 6.95 (d, J=8.3, 2H), 7.21 (dd, J=1.7,8.0, 1H), J=1.7, 1H), 7.94 (d, J=8.4, 1H), 7.96 (t, J=5.5, 1H), 8.37 (t, J 5.7, 1H), 8.50-8.85 (br s, 2H), 9.05-9.22 (br s, 2H), 9.20-9.60 (br s, 1H).
Example 41
N-[N′-[N″-(3″,4″-dihydroxybenzoyl)-L-tyrosyl]-L-γ-O-benzyl-aspartyl]-dopamine
Step A. N-Boc-L-aspartyl-dopamine γ-benzyl ester trifluoroacetate
Coupling of N-Boc-L-aspartic acid γ-benzyl ester (1.50 g, 4.63 mmol) dopamine hydrochloride by following the indications of example 6. Purification by flash chromatography eluting with 50% ethyl acetate in hexane afforded 2.06 g (93%) of the title compound after eluting with 40% ethyl acetate in hexane.
1 H NMR (DMSO-d 6 ): 1.37 (s, 9H), 2.45-2.52 (m, 2H) 2.57 (dd, J=8.6, 15.9, 1H), 2.70-2.78 (m, 1H), 3.10-3.25 (m, 2H), 4.28-4.35 (m, 1H), 5.08 (s, 2H), 6.41 (d, J=7.9, 1H), 6.65 (s, 1H), 6.62 (d, J−7.9, 1H), 7.04 (d, J=7.8, 1H), 7.29-7,40 (m, 5H), 7.80 (s, 1H), 8.62 (s, 1H), 8.71 (s, 1H).
Step B. N-[N′-[N″-(3″,4″-dihydroxybenzoyl)-L-tyrosyl]-L-γ-O-benzyl-aspartyl]-dopamine
The product obtained in step A of this example (500 mg, 1.00 mmol) was hydrolyzed by following the indications of example 3. The resulting product was then coupled with N-3,4-dihydroxybenzoyl-L-tyrosine as indicated in example 6. Purification by flash chromatography eluting with 5% methanol in methylene chloride containing 1% acetic acid afforded 69 mg (35%) of the desired title compound.
1 H NMR (DMSO-d 6 ): 2 signal sets 2.45-2.67 (m, 3H), 2.75-2.98 (m, 3H), 3.10-3.25 (m, 2H), 4.39-4.52 (m, 1H), 4.57-4.69 (m, 1H), 5.04-5.06 (m, 2H), 6.42 (d, J=7.6, 1H), 6.57-6.76 (m, 4H), 7.05-7.35 (m, 7H), 7.71 (t, J=5.5, 1H), 7.93 (t, J=5.5, 1H), 8.12 (d, J−7.6, 1H), 8.26 (d, J=7.7, 1H), 8u.63 (s, 1H), 8.73 (s, 1H), 9.10 (s, 1H), 9.20 (s, 1H), 9.51 (s, 1H).
Example 42
Preparation of N-[N′-(3′,4′-dihydroxyhydrocinnamoyl)-L-tyrosyl]-L-tyrosine
Step A. N-3,4-dihydroxyhydrocinnamoyl-O-benzyloxy-L-tyrosine
O-benzyloxy-L-tyrosine benzyl ester p-toluenesulfonate salt (1.01 g. 1.9 mmol) was coupled with 3,4-dihydroxyhydrocinnamoic acid following the indications of example 4. Purification by flash chromatography eluting with 50% ethyl acetate in hexane afforded 855 mg (84%) of the pure amide.
1 H NMR (DMSO-d 6 ): 2.29 (t, J=7.8, 2H), 2.55 (t, J=7.8, 2H), 2.85 (dd, J=8.5, 7.6, 1H), 2.94 (dd, J=6.1, 13.8, 1H), 4.45 (ddd, J=6.1, 8.9, 7.6, 1H), 5.03-5.09 (m, 4H), 6.39 (d, J=8.0, 1H), 6.5 6 (s, 1H), 6.61 (s, 1H), 6.8 8 (d, J=8.2, 2H), 7.07 (d, J=8.2, 2H), 7.27 (d, J=7.0, 2H), 7.30-7.40 (m, 8H), 7.43 (d, J=7.5, 1H), 8.29 (d, J=7.6, 1N), 8.61 (s, 1H).
Step B. N-3,4-dihydroxyhydrocinnamoyl-L-tyrosine
The deprotection of the amide was carried out using the conditions outlined in example 5. Purification by flash chromatography eluting with 10% methanol in dichloromethane afforded 190 mg (73%) of the title compound.
1 H NMR (DMSO-d 6 ): 2.27 (t, J=7.9, 2H), 2.53 (t, J=7.9, 2H), 2.72 (dd, J=9.4, 13.7, 1H), 2.89 (dd, J=5.0, 13.7, 1H), 4.33 (ddd, J=5.0, 9.4, 8.2, 1H), 6.39 (d, J=7.3, 1H), 6.55 (s, 1H), 6.59 (d, J=7.3, 1H),6.64 (d, J=8.1, 2H), 6.97 (d, J=8.1, 2H), 8.04(d,J=8.2, 1H), 8.4-8.9 (br s, 2H), 12-13 (br s, 1H).
Step C. N-[N′-(3′,4′-dihydroxyhydrocinnamoyl)-L-tyrosyl]-L-tyrosine
The product obtained in step B of this example (48 mg, 0.14 mmol) was coupled with O-benzyloxy-L-tyrosine benzyl ester p-toluenesulfonate salt following the indications of example 4. Purification by flash chromatography eluting with 4% methanol in ethyl acetate containing 1% acetic acid afforded 68 mg (100%) of the pure title compound.
1 H NMR (DMSO-d 6 ): 2.21 (t, J=8.4, 2H), 2.47 (t, J=8.4, 2H), 2.57 (dd, J=9.9, 14.2, 1H), 2.80 (dd, J=7.9, 14.0, 1H), 2.86 (dd, J=3.3, 14.2, 1H), 2.93 (dd, J=4.9, 14.0, 1H), 4.33 (ddd, J=4.9, 7.9, 7.6, 1H), 4.44 (ddd, J=3.3, 9.9, 8.2, 1H), 6.36 (d, J=7.9, 1H), 6.54 (s, 1H), 6.59 (d, J=7.9, 1H), 6.61 (d, J=8.1, 2H), 6.65 (d, J=7.9, 2H), 6.98 (d, J=8.1, 2H), 7.00 (d, J=7.9, 2H), 7.90 (d, J=8.2, 1H), 8.05 (d, J=7.6, 1H), 8.57 (s, 1H), 8.60-8.80 (br s, 1H), 9.11 (s, 1H), 9.18 (s, 1H), 12.1-12.9 (br s, 1H).
Example 43
Preparation of N-[N′-[N″-(3″,4″-dihydroxyhydrocinnamoyl)-L-tyrosyl]-L-tyrosyl]-dopamine
The product obtained in step A of example 42 (100 mg, 0.29 mmol) was coupled with O-2,6-dichlorobenzyloxy-L-tyrosyl-dopamine salt following the indications of example 4. The crude material (315 mg) was used as isolated and subjected to hydrogenolysis using the conditions of example 5. Purification by flash chromatography eluting with 7% methanol in ethyl acetate containing 1% acetic acid afforded 100 mg (54%) of the pure title compound.
1 H NMR (DMSO-d 6 ): 2.42-2.50 (m, 2H), 2.58-2.65 (m, 2H), 2.69-2.76 (m, 2H), 2.79 (dd, J=8.3, 14.0, 1H), 2.85 (dd, J=8.0, 13.8, 1H), 2.96 (dd, J=6.3, 14.0, 1H), 3.03 (dd, J=6.2, 13.9, 1H), 3.29-3.42 (m, 2H), 4.47-4.53 (m, 1H), 4.53-4.59 (m, 1H), 6.52-6.59 (m, 2H), 6.69-6.80 (m, 8H), 7.02 (d, J=8.2, 2H), 7.06 (d, 8.5, 2H),
Example 44
Preparation of N′-(3′,4′-dihydroxyhydrocinnamoyl)-L-3,4-dihydroxyphenylalanine
Step A. N′-(3′,4′-dihydroxyhydrocinnamoyl)-L-3,4-O-dibenzyloxyphenylalanine benzyl ester
The title compound was prepared by cleaving the Boc protecting group of the product prepared in step B of the example 16 (310 mg, 0.80 mmol) and coupling it with 3,4-dihydroxyhydrocinnamic acid as described in example 3 and in example 4 respectively. Purification by flash chromatography using 5% MeOH/CH 2 Cl 2 containing 1% acetic acid yielded 220 mg (61%) of the desired product.
1 H NMR (DMSO-d 6 ): 2.29 (t, J=8.0, 2H), 2.55 (t, J=8.0, 2H), 2.73 (dd, J=8.5, 13.8, 1H), 2.82 (dd, 6.4, 13.8, 1H), 4.41 ddd, J=6.4, 8.5, 7.5, 1H), 5.03 (d, J=12.6, 1H), 6.56 (s, 1H), 6.60 (s, 1H), 6.60 (d, J=8.5, 1H), 6.61 (d, J=7.7, 1H), 7.22-7.38 (m, 5H), 8.26 (d, J=7.5, 1H), 8.4-9.2 (br s, 4H).
Step B. N′-(3′,4′-dihydroxyhydrocinnamoyl)-L-3,4-dihydroxyphenylalanine
The title compound was prepared by the reduction of the compound obtained in step A of this example (135 mg, 0.30 mmol) according to the indications found in example 5. The product (90 mg, 83%) was obtained by filtering off the catalyst and evaporating the filtrate to dryness.
1 H NMR (DMSO-d 6 ): 2.27 (t, J=8.0, 2H), 2.55 (t, J=8.0, 2H), 2.65 (dd, J=8.6, 13.5, 1H), 2.66 (dd, 3.5, 13.5, 1H), 4.26 ddd, J=3.5, 8.6, 7.5, 1H), 6.39 (d, J=8.3, 1H), 6.41 (d, J=8.5, 1H), 6.56-6.60 (m, 4H), 7.82 (d, J=5.9, 1H), 8.0-9.7 (br s, 4H).
Example 45
Preparation of N′-[N″-(3″,4″-dihydroxyhydrocinnamoyl)-L-3′,4′-dihydroxyphenylalanyl]-L-3,4-dihydroxyphenylalanine
Boc-L-3,4-di-O-benzyloxyphenylalanine benzyl ester (325 mg, 0.68 mmol) was deprotected by treatment with TFA as indicated in example 3, providing the desired L-diO-benzyloxyphenylalanine benzyl ester that was coupled with Boc-L-dihydroxyphenylalanine following the indications of example 6. Purification by flash chromatography eluting with 2% methanol in methylene chloride afforded 275 mg (62%) of the dipeptide intermediate. Subsequent removal of the Boc group, again following the indications of example 3, provided the intermediate that was coupled with 3,4-dihydroxyhydrocinnamic acid as indicated in example 4. The coupled product was hydrogenolyzed as isolated according to the indications of example 5. Purification by flash chromatography eluting with 7% methanol in ethyl acetate containing 1% acetic acid provided 75 mg (35%) of the title compound.
1 H NMR (DMSO-d 6 ): 2.22 (t, J=8.0, 2H), 2.46-2.53 (m, 3H), 2.74 (dd, J=8.1, 13.5, 1H), 2.80-2.85 (m, 1H), 2.86 (dd, 5.3, 13.5, 1H), 4.31 ddd, J=8.1, 5.3, 7.2, 1H), 4.38-4.46 (m, 1H), 6.37 (d, J=7.8, 1H), 6.43-6.49 (m, 2H), 6.54 (s, 1H), 6.56-6.63 (m, 4H), 6.64 (s, 1H), 7.93 (d, J=8.3, 1H), 8.01 (d, J=7.2, 1H), 8.5-8.9 (br s, 6H), 12.2-12.8 (br s, 1H).
Example 46
Preparation of N-[N′-[3′,4′-dihydroxyhydrocinnamoyl)-L-3,4-dihydroxyphenylalanyl]-dopamine
Step A. N-Boc-3,4-dihydroxyphenylalanyl-dopamine
N-Boc-L-3,4-dihydroxyphenylalanine (1.00 g, 3.36 mmol) was coupled with dopamine hydrochloride according to the indications of example 6. Purification by flash chromatography eluting with 5% methanol in methylene chloride containing 1% acetic acid provided 1.17 g (83%) of the pure coupled product.
1 H NMR (DMSO-d 6 ): 1.32 (s, 9H), 2.44-2.52 (m, 2H), 2.53 (dd, J=9.7, 13.5, 1H), 2.71 (dd, J=4.3, 13.5, 1H), 3.07-3.28 (m, 2H), 3.98 (ddd, J=4.3, 9.7, 8.3, 1H), 6.42 (d, J=7.8, 1H), 6.45 (d, J=8.0, 1H), 6.57-6.63 (m, 4H), 6.64 (d, J=8.3, 1H), 7.80 (t, J=5.0, 1H), 8.0-9.8 (br s, 4H).
Step B. N-[N′-[N″-[3″,4″-dihydroxyhydrocinnamoyl)-L-3′,4′-dihydroxyphenylalanyl]-L-3,4-dihydroxyphenylalanyl]-dopamine
The product of step A of this example (1.17 g, 2.79 mmol) was treated with TFA as in example 3 to remove the Boc protecting group. A portion of the product thus obtained (260 mg, 0.60 mmol) was then coupled with 3,4-dihydroxyhydrocinnamic acid using the conditions as in example 4. Purification by flash chromatography eluting with 10% methanol in ethyl acetate containing 1% acetic acid provided 113 mg (38%) of the desired product.
1 H NMR (DMSO-d 6 ): 2.26 (t, J=7.7, 2H), 2.42-2.48 (m, 2H), 2.52 (t, J=7.7, 2H), 2.54 (dd, J=8.0, 13.6, 1H), 2.73 (dd, J=5.0, 13.6, 1H), 3.05-3.24 (m, 2H), 4.31 (ddd, J=5.0, 9.0, 8.3, 1H), 6.37 (d, J=8.0, 1H), 6.39-6.43 (m, 2H), 6.55-6.63 (m, 6H), 7.79 (t, 4.9, 1H), 7.91 (d, J=8.3, 1H), 7.4-10.0 (br s, 6H).
Example 47
Preparation of N-[N′-[N′-(3″,4″-dihydroxyhydrocinnamoyl]-L-3′,4′-dihydroxyphenylalanyl]-L-3,4-dihydroxyphenylalanyl]-dopamine
The product obtained in step A of example 46 (355 mg, 0.58 mmol) was deprotected by treating with TFA according to the indications of example 3. The product thus obtained was coupled with 3,4-dihydroxyhydrocinnamic acid according to the conditions of example 4. Purification by flash chromatography eluting with 5% methanol in ethyl acetate containing 1% acetic acid provided 70 mg (18%) of the title compound.
1 H NMR (DMSO-d 6 ): 2.22-2.28 (m, 2H), 2.45 (t, J=6.8, 2H), 2.46-2.57 (m, 3H), 2.62 (dd, J=8.3, 13.6, 1H), 2.71-2.80 (m, 2H), 3.06-3.21 (m, 2H), 4.25-4.32 (m, 1H), 4.32-4.40 (1H), 6.33-6.46 (m, 4H), 6.54-6.67 (m, 8H), 7.74 (t, J=5.0, 1H), 7.83 (d, J=8.0, 1H), 8.00 (d, J=8.0, 1H), 2.8-4.7 (br s, 8H).
Example 48
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-DL-3-fluorotyrosinyl]-dopamine
Step A. N′-3′,4′-dihydroxybenzoyl-O-benzyl-DL-3-fluorotyrosine benzyl ester
N-Boc-O-benzyl-DL-3-fluorotyrosine benzyl ester (524 mg, 1.09 mmol) was deprotected by treating with TFA as indicated in example 3, providing the crude intermediate that was coupled with 3,4-dihydroxybenzoic acid as indicated in example 4. Purification of the product eluting with 15% ethyl acetate in methylene chloride provided 205 mg (34%) of the desired amide product.
1 H NMR (acetone-d 6 ): 3.17 (dd, J=5.6, 5.0, 2H), 5.13 (m, 1H), 5.13 (d, J=12, 2H), 5.23 (d, J=7.2, 2H), 6.58-7.40 (m, 16H).
Step B. N′-[(3′,4′-dihydroxybenzoyl)-DL-3-fluorotyrosyl]-dopamine
The product obtained in step A of this example (179 mg, 0.32 mmol) was unblocked by hydrogenolysis according to example 5, providing a product that was then reacted with dopamine hydrochloride according to the indications of example 6. Purification by flash chromatography eluting with 10% methanol in ethyl acetate containing 1% acetic acid provided 118 mg (71%) of the title compound.
1 H NMR (acetone-d 6 ): 2.62 (d, J=6.0, 2H), 3.25 (dd, J=5.3, 6.8, 2H), 3.38 (q, J=6.2, 2H) 4.75 (q, J=6, 1H), 6.50 (d, J=7.7, 2H), 6.60 (m, 2H), 6.83 (d, J=8.3, 1H), 6.89 (d, J=8.9, 1H), 6.90 (s, 1H), 7.05 (d, J=11.7, 1H), 7.25 (d, J=8.2, 1H), 7.37 (s, 1H).
Example 49
Preparation of N-(3,4-dihydroxybenzoyl)-δ-N′-(3′,4′-dihydroxyphenethyl)-L-glutamine α-benzyl ester
Step A. N-Boc-δ-N′-(3′,4′-dihydroxyphenethyl)-L-glutamine benzyl ester
N-Boc-L-glutamic acid α-benzyl ester (800 mg, 2.37 mmol) was coupled with dopamine hydrochloride according to example 6. Purification by flash chromatography eluting with 5% methanol in ethyl acetate containing 1% acetic acid yielded 896 mg (80%) of white crystals.
1 H NMR (acetone-d 6 ): 1.07-2.15 (m, 2H), 2.27 (t, J=6.7, 2H), 2.63 (t, 7.2, 2H), 3.35 (q, T=6.4, 2H), 4.20 (m, 1H), 5.16 (q, J=14.0, 2H), 6.45 (d, J=5.8, 1H), 6.53 (d, J=7.8, 1H), 6.70 (s, 1H), 6.72 (d, J=7.6, 1H), 7.07 (s, 1H), 7.30-7.40 (m, 5H), 7.62-7.71 (s, 2H).
Step B. N-(3,4-dihydroxybenzoyl)-δ-N′-(3′,4′-dihydroxyphenethyl)-L-glutamine α-benzyl ester
The product prepared in step A of this example (800 mg, 2.37 mmol) was deblocked with TFA as described in example 3. The product thus obtained was then coupled with 3,4-dihydroxybenzoic acid according to the indications of example 4. Purification by flash chromatography eluting with 5% methanol in ethyl acetate containing 1% acetic acid yielded 896 mg (80%) of the title compound.
1 H NMR (acetone-d 6 ): 2.15-2.26 (m, 2H), 2.39 (d, J=4.7, 2H), 2.62 (t, 7.0, 2H), 3.35 (m, 2H), 4.62 (s, 1H), 5.16 (q, J=5.2, 2H), 6.50 (d, J=7.8, 1H), 6.70 (s, 1H), 6.90 (d, J=7.9, 1H), 7.03 (dd, J=8.3, 8.7, 1H), 7.31 (dd, J=6.4, 8.9, 1H), 7.35-7.41 (m, 6H), 7.68 (q, J=9.5, 1H), 8.2 (d, J=6.6, 1H).
Example 50
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-DL-m-tyrosyl]-dopamine
Step A. Preparation of N-(tert-butoxycarbonyl)-DL-m-tyrosine
The title compound was prepared from DL-m-tyrosine (1.0 g, 5.5 mmol), by following the procedure described in example 1. The product was isolated as a colorless syrup (1.18 g, 76%).
1 H NMR (DMSO-d 6 ): 1.30 (s, 9H); 3.15 (dd, J=3.1, 13.0, 1H); 4.10 (q, J=7.2, 1H); 6.20 (d, J=8.0, 1H); 6.50-6.80 (m, 4H), 7.2 (s, 1H), 10.0 (br s, 1H).
Step B. Preparation of N-(tert-butoxycarbonyl)-O-benzyl-DL-m-tyrosine benzyl ester
The title compound was prepared from the product obtained in step A of this example (1.0 g, 3.56 mmol) according to the indications of example 2c. The crude product was purified by silica gel column chromatography using 5% MeOH/CH 2 Cl 2 to yield the desired product (1.06 g, 65%).
1 H NMR (CDCl 3 ): 1.45 (s, 9H); 3.15 (d, J=3.3, 2H); 4.15 (q, J=7.2, 1H); 4.70 (J=5.7, 1H), 5.20 (d, J=1, 4H), 6.71 (d, J=6.8, 1H); 6.8 (s, 1H), 6.90 (d, 8.5, 1H), 7.2 (t, J=7.6, 1H), 7.3-7.5 (m, 1H).
Step C. N-(3,4-dihydroxybenzoyl)-O-benzyl-DL-m-tyrosine benzyl ester
The title compound was prepared from the product obtained in step B of this example (520 mg, 1.09 mmol) by the removal of the Boc group following the indications of example 3. The resulting unblocked derivative was then coupled with 3,4-dihydroxybenzoic acid according to the indications of example 4. The crude product was purified by silica gel column chromatography using 10% ethyl acetate in methylene chloride to yield 205 mg (34%) of the desired product.
1 H NMR (DMSO-d 6 ): 3.15 (d, J=3.1, 2H); 4.20 m, 1H), 5.20 (m, 4H); 6.70-7.80 (m, 17H), 8.6 (d, J=7.2, 2H).
Step D. N-[N′-(3′,4′-dihydroxybenzoyl)-DL-m-tyrosyl]-dopamine
The title compound was prepared from the product of step C of this example (208 mg, 0.56 mmol) by removing the benzyl ester group following the indications of example 5. The resulting unblocked derivative was coupled with dopamine hydrochloride according to the indications of example 6. Purification by silica gel chromatography with 10% MeOH in ethyl acetate containing 1% acetic acid provided the desired product, (26 mg, 14%).
1 H NMR (DMSO-d 6 ): 2.62 (t, J=5.9, 2H), 3.20 (m, 2H); 4.7 (s, 1H); 6.70-7.5 (m, 12H), 8.5 (s, 1H), 9.3 (br s, 4H).
Example 51
Preparation of N-[N′-[N″-(3″,4″-dihydroxybenzoyl -L-tyrosyl]-L-tyrosyl]-dopamine
N-[N′-(3′,4′-dihydroxybenzoyl)-L-tyrosyl]-tyrosine (prepared as described in example 36, step C) (30 mg, 0.06 mmol) was coupled with dopamine hydrochloride according to the indications of example 6. Purification by flash chromatography eluting with 5% methanol in ethyl acetate containing 1% acetic acid provided 5 mg (14%) of the title compound. 1H NMR (acetone-d 6 ): 2.57 (t, J=7.0, 2H), 2.84 (dd, J=7.8, 13.6, 1H), 2.87-303 (m, 2H), 3.08 (dd, J=5.3, 13.9, 1H), 3.23-3.36 (m, 2H), 4.45-4.52 (m, 1H), 4.58-4.66 (m, 1H), 6.50 (dd, J−2.0, 7.8, 1H), 6.65 (d, J=8.3, 2H), 6.69 (d, J−7.8 1H), 6.70 (d, J=2.0, 1H), 7.07-7.11 (m, 1H), 7.10 (d, J=7.9, 2H), 7.21 (dd, J=1.9, 8.2, 1H), 7.39 (d, J=1.9, 1H), 7.40-7.46 (m, 1H), 7.55 (d, J=7.2, 1H).
The compounds listed in Table 3 were prepared following similar procedures as for the preparation of the derivatives described above (see new examples below); the number(s) in brakets after each root amino acid name is the number(s) of an example(s) below. Their activities are also listed in the same table demonstrating their potential usefulness.
TABLE 3
Anti-integrase activity (IC 50 ) of amino acid derivatives in accordance with
general formula I above
Anti-integrase activity (IC 50 )
Other Nα-3,4-
Nα-Caffeoyl
dihydroxyphenyl
Root Amino acid
derivative
derivative
(example no.)
μM
μM
L-Aspartic acid (ex. 52)
2.2
L-Tryptophan (ex. 53)
1.5
L-3,4-Dihydroxyphenylalanine (ex. 54)
0.62
L-3,4-Dihydroxyphenylalanine (ex. 55)
0.38
L-Tyrosine (ex. 56)
0.78
L-3,4-Dihydroxyphenylalanine (ex. 57)
0.106
L-Cysteine (ex. 58)
0.21
L-Serine (ex. 59)
0.14
L-Glutamic acid (ex. 60)
0.105
L-Aspartic acid (ex. 61)
3.5
L-Aspartic acid (ex. 62)
3.5
L-Glutamic acid (ex. 63)
2.8
L-Tyrosine (ex. 64)
3
For the purposes of Table 3 the HIV-1 integrase inhibition assay was based on a known procedure (Hazuda, D. J. et al., Nucleic Acids Res. 22, 1121-1122 (1994)).
Example 52
Preparation of Nα-caffeoyl-Nγ-(3-hydroxytyramine)-L-aspartic acid benzyl ester
Step A. Preparation of Nα-tert-butoxycarbonyl-Nγ-(3-hydroxytyramine)-L-aspartic acid benzyl ester
The title compound was prepared from commercially available Nα-tert-butoxycarbonyl-L-aspartic acid benzyl ester (2.0 g, 6.0 mmol), by following the procedure described in example 6. The product was isolated as a white solid (2 g, 76% yield).
1 H NMR (acetone-d 6 ): 1.4 (s, 9H), 2.6 (t, J=3.6, 2H), 2.7 and 2.80 (ABX, J=8.5, 15.0, 2H), 3.3 (d, J=3.2, 2H), 4.6 (br s, 1H), 5.2 (q, J=6.0, 2H), 6.3-7.5 (m, 10H), 7.68-7.72 (2 s, 2H).
Step B. Preparation of Nα-caffeoyl-Nγ-(3-hydroxytyramine)-L-aspartic acid benzyl ester
The title compound was prepared from the product obtained in step A of this example (958 mg, 2.0 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (565 mg, 3.1 mmol) according to the indications of example 4. The crude product was purified by flash chromatography using 30% AcOEt/CHCl 3 and 5-10% MeOH/CHCl 3 to yield the desired product (432 mg, 40%).
1 H NMR (DMSO-d 6 ): 2.5 (s, 2H), 2.6-2.7 (m, 2H), 3.2 (d, J=1.7, 2H), 4.8 (q, J=3.3, 1H), 5.1, (s, 2H), 6.3-7.0 (m, 13H), 8.0 (t, J=2.6, 1H), 8.4 (d, J=3.8, 1H), 8.5-9.4 (br s, 4H).
Example 53
Preparation of N-(N′-caffeoyl-L-tryptophanyl)dopamine
The title compound was prepared from N-(N′-tert-butoxycarbonyl-L-tryptophanyl)dopamine obtained in step A of example no. 29 (1.3 g, 2.8 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (770 mg, 4.3 mmol) according to the indications of example 4. The crude product was purified by flash chromatography using 30% AcOEt/CH 2 Cl 2 /1% AcOH and 5-10% MeOH/CH 2 Cl 2 /1% AcOH to yield the desired product (899 mg, 63%).
1 H NMR (DMSO-d 6 ): 2.4 (q, J=3.7, 2H), 2.9-3.3 (m, 4H), 4.6 (q, J=2.8, 1H), 6.3-7.7 (m, 13H), 8.1 (t, J=2.7, 1H), 8.2 (d, J=4.0, 1H), 10.0 (br s, 4H), 10.8, (s, 1H).
Example 54
Preparation of N-(N′-caffeoyl-L-3,4-dihydroxyphenylalanyl)dopamine
The title compound was prepared from N-(N′-tert-butoxycarbonyl-L-3,4-dihydroxyphenylalanyl)dopamine obtained in step A of example no. 46 (878 mg, 2.0 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (546 mg, 3.0 mmol) according to the indications of example 4. The crude product was purified by flash chromatography using 30% AcOEt/CH 2 Cl 2 /1% AcOH and 10% MeOH/CH 2 Cl 2 /1% AcOH to yield the desired product (407 mg, 41%).
1 H NMR (DMSO-d 6 ): 2.4 (s, 2H), 2.6-2.9 (m, 2H), 3.2 (m, 2H), 4.4 (m, 1H), 6.4-7.8 (m, 11H), 8.0 (m, 2H), 9.7 (br s, 6H).
Example 55
Preparation of N-(N′-caffeoyl-L-3,4-dihydroxyphenylalanyl)-3,4-dihydroxybenzylamine
Step A. Preparation of N-(N′-tert-butoxycarbonyl-L-3,4-dihydroxyphenylalanyl)-3,4-dihydroxybenzylamine
The title compound was prepared from Nα-tert-butoxycarbonyl-L-3,4-dihydroxyphenylalanine (575 mg, 1.9 mmol), by following the procedure described in example 6, using 3,4-dihydroxybenzylamine hydrobromide instead of dopamine hydrochloride. The crude material was purified by flash chromatography using 30, 50% AcOEt/CH 2 Cl 2 /1% AcOH to yield the desired product as white crystals (457 mg, 56% yield).
1 H NMR (DMSO-d 6 ): 1.3 (s, 9H), 2.5-2.8 (m, 2H), 4.2 (m, 3H), 6.4-6.8 (m, 7h), 8.2 (s, 1H), 8.7 (br s, 4H).
Step B. Preparation of N-(N′-caffeoyl-L-3,4-dihydroxyphenylalanyl)-3,4-dihydroxybenzylamine
The title compound was prepared from the product obtained in step A of this example (377 mg, 0.9 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (246 mg, 1.35 mmol) according to the indications of example 4. The crude material was purified by flash chromatography using 50, 80% AcOEt/CH 2 Cl 2 /1% AcOH to yield the desired product (120 mg, 28%).
1 H NMR (DMSO-d 6 ): 2.6-2.9 (m, 2H), 4.2 (s, 2H), 4.6 (s, 1H), 6.3-7.7 (m, 11H), 8.0 (d, J=4.0, 1H), 8.3 (d, J=2.4, 1H), 9.5 (br s, 6H).
Example 56
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-tyrosyl]-3,4-dihydroxybenzylamine
Step A. Preparation of N-(N′-tert-butoxycarbonyl-L-tyrosyl)-3,4-dihydroxybenzylamine
The title compound was prepared from commercially available Nα-tert-butoxycarbonyl-L-tyrosine (1.5 g, 5.3 mmol), by following the procedure described in example 6. The product was purified by flash chromatography using 30, 60% AcOEt/CH 2 Cl 2 to yield the title product as white crystals (1.9 g, 88% yield).
1 H NMR (DMSO-d 6 ): 1.3 (s, 9H), 2.5-2.8 (m, 2H), 4.1 (t, J=4.5, 2H), 6.4-7.0 (m, 7H, 8.2 (s, 1H), 8.7 (br s, 2H), 9.2 (s, 1H).
Step B. Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-tyrosyl]-3,4-dihydroxybenzylamine
The title compound was prepared from the product obtained in step A of this example (1.4 g, 3.3 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with 3,4-dihydroxybenzoic acid (758 mg, 5.0 mmol) according to the indications of example 4. The crude product was purified by flash chromatography using 50-80% AcOEt/CH 2 Cl 2 /1% AcOH to yield the title product as a white solid (600 mg, 40%).
1 H NMR (DMSO-d 6 ): 2.7-3.0 (m, 2H), 4.2 (s, 2H), 4.6 (s, 1H), 6.3-7.7 (m, 10H), 8.0 (d, J=3.9, 1H), 8.2 (d, J=2.4, 1H), 9.5 (br s, 5H).
Example 57
Preparation of N-[N′-(3′,4′-dihydroxyphenylacetyl)-L-3,4-dihydroxyphenylalanyl]dopamine
N-(N′-tert-butoxycarbonyl-L-3,4-dihydroxyphenylalanyl)dopamine (1.5 g, 3.4 mmol, example no. 46, step A) was deprotected with TFA as described in example 3. The product thus obtained was then coupled with 3,4-dihydroxyphenylacetic acid (865 mg, 5.0 mmol) according to the indications of example 4. Purification by flash chromatography using 40-60% AcOEt/CH 2 Cl 2 containing 1% AcOH and 5% MeOH/CH 2 Cl 2 containing 1% AcOH yielded 120 mg (7%) of the title compound as white crystals.
1 H NMR (DMSO-d 6 ): 2.4-2.8 (m, 4H), 3.0-3.4 (m, 4H), 4.3 (s, 1H), 6.3-7.3 (m, 9H), 7.7-8.0 (m, 2H), 9.2 (br s, 6H).
Example 58
Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-cysteinyl]dopamine
Step A. Preparation of N-[N′-(3,4-dihydroxybenzoyl)-S-trityl-L-cysteinyl]dopamine
Commercially available Nα-(9-fluorenylmethoxycarbonyl)-S-trityl-L-cysteine (1.7 g, 2.9 mmol) was coupled with dopamine hydrochloride according to the indications of example 6. The crude N-[N′-(9-fluorenylmethoxycarbonyl)-S-trityl-L-cysteinyl]dopamine was deprotected according to the indications of example 7. The resulting intermediate was then coupled with 3,4-dihydroxybenzoic acid (278 mg, 1.8 mmol) according to the indications of example 4. The final product was purified by flash chromatography using 20-50% AcOEt/CH 2 Cl 2 containing 1% AcOH to yield the desired derivative (644 mg, 35%) as a yellow crystals.
1 H NMR (DMSO-d 6 ): 2.5 (m, 4H), 3.2 (m, 2H), 4.4 (s, 1H), 6.3-7.4 (m, 21H), 7.8 (s, 1H), 8.2 (d, J=3.8, 1H), 8.5-9.5 (4 s, 4H).
Step B. Preparation of N-[N′-(3′,4′-dihydroxybenzoyl)-L-cysteinyl]dopamine
The title compound was prepared from N-[N′-(3,4-dihydroxybenzoyl-S-trityl-L-cysteinyl]dopamine describe in step A (390 mg, 0.6 mmol) by following the indications of example 3. Purification by flash chromatography using 30-60% AcOEt/CH 2 Cl 2 containing 1% AcOH gave 108 mg (45%) of the title compound as white crystals.
1 H NMR (DMSO-d 6 ): 2.5 (m,4H), 3.2 (m, 2H), 4.4 (br s, 2H), 6.3-7.5 (m, 6H), 7.7 (s, 1H), 8.2 (d, J=4.0, 1H), 8.6-9.5(4 s, 4H).
Example 59
Preparation of N-(N′-caffeoyl-L-seryl)dopamine
Step A. Preparation of N-(N′-tert-butoxycarbonyl-L-seryl)dopamine
The title compound was prepared from Nα-tert-butoxycarbonyl-L-serine (2.5 g, 12.0 mmol), by following the procedure described in example 6. The crude material was purified by flash chromatography using 30% AcOEt/CH 2 Cl 2 and 5% MeOH/CH 2 Cl 2 to yield the desired product as white crystals (1.6 g, 40% yield).
1 H NMR (DMSO-d 6 ): 1.4 (s, 9H), 2.5 (s, 2H), 3.1-3.3 (m, 2H), 3.5 (s, 2H), 3.9 (s. 1H, 4.8 (s, 1H), 6.4-6.7 (m, 4H), 7.8 (s, 1H), 8.6 and 8.7 (2 s, 2H).
Step B. Preparation of N-(N′-caffeoyl-L-seryl)dopamine
The title compound was prepared from the product obtained in step A of this example (796 mg, 2.3 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (633 mg, 3.5 mmol) according to the indications of example 4. The crude material was purified by flash chromatography using 30% AcOEt/CH 2 Cl 2 and 5-10% MeOH/CH 2 Cl 2 to yield the desired product (282 mg, 30%) as yellow crystals.
1 H NMR (DMSO-d 6 ): 2.5 (d, J=4.0, 2H), 3.2 (s, 2H), 3.6 (s, 2H), 4.4 (s, 1H), 6.4-7.3 (m, 8H), 7.8 (s, 1H), 8.0 (m, 1H), 9.3 (br s, 5H).
Example 60
Preparation of N-[N′-caffeoyl-Nα-(3-hydroxytyramine)-L-glutamyl]dopamine
Step A. Preparation of Nα-tert-butoxycarbonyl-L-glutamic acid
The title compound was prepared from commercially available Nα-tert-butoxycarbonyl-L-glutamic acid benzyl ester (1.0 g, 3.0 mmol), by following the procedure described in example 5. The crude material was purified by flash chromatography using 30% AcOEt/CH 2 Cl 2 /1% AcOH to yield the desired product as a white powder (680 mg, 93% yield).
Step B. Preparation of N-[N′-tert-butoxycarbonyl-Nδ-(3-hydroxytyramine)-L-glutamyl]dopamine
Nα-tert-butoxycarbonyl-L-glutamic acid (718 mg, 2.9 mmol) was coupled with dopamine according to the indications of example 6. The product was purified by flash chromatography using 15, 30% AcOEt/CH 2 Cl 2 containing 1% AcOH and 10% MeOH/CH 2 Cl 2 containing 1% AcOH to yield the desired product as a white powder (1.1 g, 76% yield).
1 H NMR (DMSO-d 6 ): 1.3 (s, 9H), 1.7-2.0 (m, 4H), 2.5 (s, 4H), 3.2 (m, 4H), 3.9 (d, J=1.9, 1H), 6.3-6.8 (m, 7H), 7.8 (d, J=2.4, 2H), 9.5 (br s, 4H).
Step C. Preparation of N-[N′-caffeoyl-Nδ-(3-hydroxytyramine)-L-glutamyl]dopamine
The title compound was prepared from the product obtained in step B of this example (721 mg, 1.4 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (335 mg, 2.0 mmol) according to the indications of example 4. The crude product was purified by flash chromatography using 50, 60% AcOEt/CH 2 Cl 2 and 10% MeOH/CH 2 Cl 2 to yield the desired product (484 mg, 60%) as yellow crystals.
1 H NMR (DMSO-d 6 ): 1.7-2.0 (m, 2H), 2.1 (s, 2H), 2.5 (s, 4H), 3.2 (m, 4H), 4.3 (m, 1H, 6.4-7.6 (m, 11H), 8.0 (m, 3H), 9.4 (br s, 6H).
Example 61
Preparation of N-(N′-caffeoyl-Oγ-benzyl-L-aspartyl)dopamine
Step A. Preparation of N-(N′-tert-butoxycarbonyl-Oγ-benzyl-L-aspartyl)dopamine
The title compound was prepared from commercially available Nα-tert-butoxycarbonyl-Oγ-benzyl-L-aspartic acid (3.0 g, 9.3 mmol), by following the procedure described in example 6. The product was isolated as a white solid (2.7 g, 64% yield).
1 H NMR (acetone-d 6 ): 1.5 (s, 9H), 2.76 (t, J=3.5, 2H), 2.95 and 3.05 (ABX, J=5.5, 13.0, 4H), 4.6 (d, J=3.0, 1H), 5.2 (s, 2H), 6.4-7.6 (m, 10H), 8.5 (br s, 2H).
Step B. Preparation of N-(N′-caffeoyl-Oγ-benzyl-L-aspartyl)dopamine
The title compound was prepared from the product obtained in step A of this example (1.0 g, 2.4 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (640 mg, 3.5 mmol) according to the indications of example 4. The crude product was purified by flash chromatography using 30% AcOEt/CHCl 3 and 5% MeOH/CHCl 3 to yield the desired product as a yellow powder (549 mg, 45%).
1 H NMR (acetone-d 6 ): 2.6 (d, J=2.7, 2H), 2.8-3.0 (m, 4H), 3.4 (d, J=2.9, 2H), 4.9 (d, J=3.2, 1H), 5.1 (s, 2H), 6.4-7.6 (m, 11H), 8.2 (br s, 6H).
Example 62
Preparation of N-(N′-caffeoyl-L-aspartyl)dopamine
Step A. Preparation of N-(N′-benzyloxycarbonyl-Oγ-tert-butyl-L-aspartyl)dopamine
The title compound was prepared from commercially available Nα-benzyloxycarbonyl-Oγ-tert-butyl-L-aspartic acid (2.5 g, 7.7 mmol), by following the procedure described in example 6. The crude material was purified using 20, 50% AcOEt/CH 2 Cl 2 . The product was isolated as a white solid (3.2 g, 91% yield).
1 H NMR (DMSO-d 6 ): 1.3 (s, 9H), 2.3-2.7 (m, 4H), 3.2 (s, 2H), 4.3 (d, J=2.6, 1H), 4.8 and 5.3 (ABX, J=5.6, 16.0, 2H), 6.3-7.4 (m, 8H), 7.5 (d, J=4.0, 1H), 7.9 (s, 1H), 8.6 and 8.7 (2×s, 2×OH).
Step B. Preparation of N-(N′-caffeoyl-Oγ-tert-butyl-L-aspartyl)dopamine
N-(N′-benzyloxycarbonyl-Oγ-tert-butyl-L-aspartyl)dopamine (1.0 g, 2.3 mmol) was deprotected by hydrogenolysis as described in example 5. The product thus obtained was then coupled with caffeic acid (621 mg, 3.5 mmol) according to the indications of example 4. Purification by flash chromatography using 30-50% AcOEt/CH 2 Cl 2 containing 1% AcOH yielded 519 mg (47%) of the title compound as yellow crystals.
1 H NMR (DMSO-d 6 ): 1.3 (s, 9H), 2.4-2.7 (m, 4H), 3.2 (m, 2H), 4.7 (d, J=6.8, 1H), 6.4 -7.4 (m, 8H), 8.0 (s, 1H), 8.3 (d, J=8.0, 1H), 8.5-9.5 (br s,4H).
Step C. Preparation of N-(N′-caffeoyl-L-aspartyl)dopamine
The title compound was prepared from the product obtained in step B of this example (333 mg, 0.7 mmol) according to the indications of example 3, for 2 h. The crude product was purified by flash chromatography using 50-99% AcOEt/CH 2 Cl 2 containing 1% AcOH to yield the desired product (200 mg, 60%).
1 H NMR (DMSO-d 6 ): 2.4-2.8 (m, 4H), 3.2 (s, 2H), 4.7 (d, J=2.6, 1H), 6.3-7.4 (m, 8H), 7.9 (s, 1H), 8.3 (s, 1H), 9.7 (br s, 4×OH), 13.0 (br s, 1H).
Example 63
Preparation of Nα-(3,4-dihydroxybenzoyl)-Nδ-(3-hydroxytyramine) L-glutamic acid
The title compound was prepared from N-(3,4-dihydroxybenzoyl)-δ-N′-(3,4-dihydroxyphenethyl)-L-glutamine α-benzyl ester obtained in step B of example no. 49 (266 mg, 0.5 mmol) according to the indications of example 5. The crude product was purified by flash chromatography using 30% AcOEt/CH 2 Cl 2 /1% AcOH and 10% MeOH/CH 2 Cl 2 /1% AcOH to yield the desired product (208 mg, 95%) as white crystals.
1 H NMR (DMSO-d 6 ): 1.9-2.4 (m, 4H), 2.5 (t, J=7.0, 2H), 3.5 (d, J=5.0, 2H), 4.2 (s, 1H), 6.3-7.4 (m, 6H), 8.2 (s, 1H), 8.4 (d, J=6.0, 1H), 9.7 (br s, 4H), 12.0 (br s, 1H).
Example 64
Preparation of N-(N′-caffeoyl-L-tyrosyl)-3,4-dihydroxybenzylamine
The title compound was prepared from N-(N-tert-butoxycarbonyl-L-tyrosyl)-3,4-dihydroxybenzylamine (example 56, step A) (1.4 g, 3.3 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (978 mg, 5.4 mmol) according to the indications of example 4. The crude product was purified by flash chromatography using 40-80% AcOEt/CH 2 Cl 2 containing 1% AcOH to yield the title product as yellow crystals (784 mg, 47%).
1 H NMR (DMSO-d 6 ): 2.7-3.0 (m, 2H), 4.1 (s, 2H), 4.6 (s, 1H), 6.3-7.4 (m, 12H), 8.2 (s, 1H), 8.4 (s, 1H), 9.5 (br s, 5H).
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An hydroxyphenyl derivative selected from the group consisting of a compound of formula
and when a compound of formula I comprises a carboxylic acid group pharmaceutically acceptable salts thereof and when a compound of formula I comprises an amino group pharmaceutically acceptable ammonium salts thereof, wherein n is 1, 2 or 3, e is 1, 2 or 3, Hal represents a halogen atom (e.g. Cl, Br, F or I), p is 0, 1 or 2, r is 0, 1 or 2, X and X′ each independently represents a single bond, a saturated straight or branched hydrocarbon group of 1 to 4 carbon atoms or a straight or branched hydrocarbon group of 2 to 4 carbon atoms comprising a carbon to carbon double bond, R a represents H or —CH 3 , and R aa represents H or —CH 3 ; W may represent an amino acid residue or fragment. These compounds may be used to inhibit the activity of HIV integrase.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Patent Application Ser. No. 60/694,741, filed Jun. 28, 2005, the complete disclosure of which is hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to compounds useful for increasing cellular ATP binding cassette transporter ABCA1 production in mammals, and to methods of using such compounds in the treatment of coronary artery diseases, dyslipidiemias and metabolic syndrome. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Cholesterol is essential for the growth and viability of higher organisms. It is a lipid that modulates the fluidity of eukaryotic membranes, and is the precursor to steroid hormones such as progesterone, testosterone, and the like. Cholesterol can be obtained from the diet, or synthesized internally in the liver and intestine. Cholesterol is transported in body fluids to tissues by lipoproteins, which are classified according to increasing density. For example, low density lipoprotein cholesterol (LDL) is responsible for transport of cholesterol to and from the liver and to peripheral tissue cells, where LDL receptors bind LDL, and mediate its entry into the cell.
Although cholesterol is essential to many biological processes in mammals, elevated serum levels of LDL cholesterol are undesirable, in that they are known to contribute to the formation of atherosclerotic plaques in arteries throughout the body, which may lead, for example, to the development of dyslipidemia and coronary artery diseases. Conversely, elevated levels of high density lipoprotein cholesterol (HDL-C) have been found, based upon human clinical data and animal model systems, to protect against development of coronary diseases. Low high density lipoprotein (HDL) is also a risk factor and marker for the development of metabolic syndrome and insulin resistance.
In general, excess cholesterol is removed from the body by a pathway involving HDL. Cholesterol is “effluxed” from cells by one of two processes—either by transfer to mature HDL, or an active transfer to apolipoprotein A-1 (Apo A-I). Transfer to mature HDL may involve both active and passive transfer mechanism. Transfer to Apo A-I and the generation of nascent HDL is mediated by ABCA1. In this process, lipid-poor HDL precursors acquire phospholipid and cholesterol forming nascent HDL which can then converted to mature HDL through the action of multiple plasma enzymes and the acquisition of cholesterol from peripheral tissues. HDL cholesterol is eventually transported to the liver where it is either recycled or excreted as bile. This process is often referred to as “reverse cholesterol transport”.
One method of treatment aimed at reducing the risk of formation of atherosclerotic plaques in arteries relates to modifying plasma lipid and lipoprotein levels to desirable levels. Such methods includes diet changes, and/or treatment with drugs such as derivatives of fibric acid (clofibrate, gemfibrozil, and fenofibrate), nicotinic acid, and HMG-CoA reductase inhibitors, such as mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, rosuvastatin, and lovastatin, which reduce plasma LDL cholesterol levels by either inhibiting the intracellular synthesis of cholesterol or inhibiting the uptake via LDL receptors. In addition, bile acid-binding resins, such as cholestyramine, colestipol and probucol decrease the level of LDL-cholesterol by reducing intestinal uptake and increasing the catabolism of LDL-cholesterol in the liver. Nicotinic acid through a poorly defined mechanism increase HDL levels and decreases triacylglycerol levels.
Another method of reducing the risk of formation of atherosclerotic plaques involves increasing the rate of cholesterol efflux from tissues and the formation of nascent HDL by increasing ABCA1 gene expression. The nuclear hormone receptor LXR is a key physiologic modulator of ABCA1 expression, and effectors of the LXR receptor may be used to pharmacologically increase ABCA1 activity. In addition to regulating ABCA1, LXR has been shown to at least partially regulate LXR target genes identified in macrophages, liver, intestine and other sites, which serve to orchestrate a concerted physiological response to excess sterol deposition. These include at least three other members of the ABC transporter family. Two of which have been identified as agents for another rare genetic disorder of sterol metabolism termed sitosterolemia. Another has been implicated as potential transporter of cellular cholesterol to mature and maturing HDL.
Unfortunately, systemic administration of potent full LXR ligands causes increased plasma triglycerides and liver lipid deposition due to the induction of several gene products involved in the synthesis of fats. Lipogenic genes in the liver are highly induced by LXR activation either directly, or via LXR induced transcription of the sterol regulatory protein SREBP1c. Selective LXR activation in macrophages, however, may have a protective role in reverse cholesterol transport while avoiding the pitfalls of inducing lipid bio-synthetic genes in the liver.
Additional advantages may be afforded by selectively interfering with the LXR enhancer/promoter transcription complex with LXR ligands that increase transcription of the subset of LXR target genes involved in cholesterol transport, but not the lipid bio-synthetic target genes. Tissue selective and/or unique partial LXR agonists may also provide the beneficial induction of ABCA1 (and other target genes) in macrophages and other non-hepatic tissues, while causing no or limited induction of SREBP1c and other lipogenic genes in the liver. See, for example Joseph S. B. and Tontonoz, P. (2003) Current Opinion in Pharmacology, 3:192-197 and Brewer H. B. et al. (2004) Arterioscler. Thromb. Vasc. Biol., 24:1755-1760.
It is desired to provide alternative therapies aimed at reducing the risk of formation of atherosclerotic plaques in arteries, especially in individuals deficient in the removal of cholesterol from artery walls via the HDL pathway. HDL cholesterol levels are a steady state measurement determined by the relative rates of HDL production and HDL clearance. Multiple enzymes and mechanisms contribute to both production and clearance. One method of increasing HDL levels would be to increase the expression of ABCA1 and the generation of nascent HDL resulting in increased HDL production. Accordingly, it is desired to provide compounds that are stimulators of the expression of ABCA1 in mammals both to increase cholesterol efflux and to raise HDL cholesterol levels in blood. This would be useful for the treatment of various disease states and dyslipidemias characterized by low HDL levels, such as coronary artery disease and metabolic syndrome.
It has also been shown that a combination of a drug that decreases LDL cholesterol levels and a drug that increases HDL cholesterol is beneficial; see, for example, Arterioscler., Thromb., Vasc. Biol. (2001), 21(8), 1320-1326, by Marian C. Cheung et al. Accordingly, it is also desired to provide a combination of a compound that stimulates the expression of ABCA1 with a compound that lowers LDL cholesterol levels.
It should be noted it has also been shown that raising production in macrophages locally reduces cholesterol deposition in coronary arteries without significantly raising plasma HDL cholesterol and without effecting cholesterol production by the liver. In this instance, raising ABCA1 expression is beneficial even in the absence of increased HDL cholesterol such that selective non-hepatic upregulation of ABCA1 may have beneficial effects on coronary artery disease in the absence of measurable effects on plasma lipid and lipoprotein levels.
SUMMARY OF THE INVENTION
It is an object of this invention to provide compounds capable of increasing ABCA1 expression. Accordingly, in a first aspect, the invention relates to compounds of Formula I:
wherein:
R 1 and R 2 are independently optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; or R 1 and R 2 when taken together with the carbon atom to which they are attached represent a 5 or 6 membered carbocyclic or heterocyclic ring; R 3 , R 4 and R 5 are independently hydrogen, hydroxyl, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, cyano, halo, —SO 2 —NR 9 R 10 , or —C(O)R 11 , in which R 9 and R 10 are independently hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or may joint to form a 5 or 6 membered optionally substituted heterocyclic ring, and R 11 is —OH or optionally substituted lower alkoxy; R 6 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, —C(O)R 12 , or —S(O) 2 R 13 , in which R 12 is optionally substituted lower alkyl, lower alkoxy or —NR 14 R 15 , in which R 13 , R 14 , and R 15 are independently hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, or R 14 and R 15 may join to form a 5 or 6 membered optionally substituted heterocyclic ring; R 7 is hydrogen, hydroxyl, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or —NR 14 R 15 ; and R 8 is hydrogen, cyano, optionally substituted lower alkyl, optionally substituted heterocyclyl, optionally substituted phenyl, —C(O)R 11 , —C(O)R 14 , —SR 13 , —OR 14 , —NR 9 S(O) 2 R 10 , —NR 14 C(O)NR 14 R 15 , —C(O)NR 14 R 15 , —CH 2 C(O)R 11 , —S(O) 2 R 13 , —B(OH) 2 , —C(CF 3 ) 2 OH, —CH 2 P(O)(R 11 ) 2 , halo, —NHC(O)R 14 , —N[(CH 2 ) 2]2 SO 2 , or —S(O) 2 NR 9 R 10 ; or R 7 and R 8 may join together to form an optionally substituted 5 or 6 membered heterocyclic or heteroaryl ring; R 20 is hydrogen, cyano, hydroxyl, halo, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —NR 14 R 15 , —C(O)R 11 , —C(O)R 14 , —SR 14 , —OR 14 , —C(S)R 11 , —C(S)R 14 , —NR 9 S(O) 2 R 10 , —NR 14 C(O)NR 14 R 15 , —C(O)NR 14 R 15 , —C(S)NR 14 R 15 , —CH 2 C(O)R 11 , —S(O) 2 R 13 , B(OH) 2 , —C(CF 3 ) 2 OH, —CH 2 P(O)(R 11 ) 2 , —NHC(O)CH 3 , —N[(CH 2 ) 2 ] 2 SO 2 , or —S(O) 2 NR 9 R 10 ; A and D are independently 5 or 6 membered monocyclic heterocyclic, monocyclic heteroaryl, or monocyclic aryl rings; and X is oxygen, sulfur, —S(O)—, —S(O) 2 — or —NR 16 —, in which R 16 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, —C(O)R 12 , or —S(O) 2 R 13 .
In a second aspect, the invention relates to a method for using the compounds of Formula I in the treatment of a disease or condition in a mammal that can be treated with a compound that elevates serum levels of HDL-C, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, diseases of the artery, in particular coronary artery disease, metabolic syndrome and diabetes.
In a third aspect, the invention relates to a method for using the compounds of Formula I in the treatment of a disease or condition in a mammal that can be treated with a compound that promotes cholesterol efflux from cells, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, diseases of the artery, in particular coronary artery disease.
In a fourth aspect, the invention relates to a method for using the compounds of Formula I in the treatment of a disease or condition characterized by low HDL-C in a mammal that can be treated with a compound that elevates serum levels of HDL-C, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, diseases of the artery, in particular coronary artery disease, and diabetes.
A fifth aspect of this invention relates to pharmaceutical formulations, comprising a therapeutically effective amount of a compound of Formula I and at least one pharmaceutically acceptable excipient.
A sixth aspect of this invention relates to methods of preparing the compounds of Formula I.
At present, preferred compounds of the invention include, but are not limited to:
2-(2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((6aS,12aR)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)acetic acid;
2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
methyl 2-bromo-10-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylate;
1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
2-[7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-[(12aS,6aS)-7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydrochromano[4,3 -b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;
3-methylbut-2-enyl (6aS,12aR)-9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;
3-methylbut-2-enyl 9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;
3-methylbut-2-enyl 7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;
3-methylbut-2-enyl 7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate;
7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylic acid;
3-methylbut-2-enyl 9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate;
7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylic acid;
9-(dihydroxyboramethyl)-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinoline-3-carboxylic acid;
1,1,1,3,3,3-hexafluoro-2-(4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;
4-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;
2-(4-ethoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
1,1,1,3,3,3-hexafluoro-2-(1 -methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
2-[7,7-dimethyl-4-(3-methylbut-2-enyloxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)acetic acid;
3-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic acid;
3-((12aR,6aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3 -b]quinolin-9-yl)propanoic acid;
4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS)-4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
2-((6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3 -hexafluoropropan-2-ol;
methyl (2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}prop-2-enoate;
(2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}—N,N-dimethylprop-2-enamide;
(6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}—N,N-dimethylpropanamide;
methyl 3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl}propanoate;
4-ethoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-(4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;
1-(1 -methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;
1-methoxy-7,7-dimethyl-9-(trifluoromethy;1)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
(6aS,12aR)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aS)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(6aS,12aR)-9-fluoro-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylic acid;
4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
1,1,1,3,3,3-hexafluoro-2-(4-fluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
((6aS,12aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-9-fluoro-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-9-ethoxy-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylic acid;
10-(1H-1,2,3,4-tetraazol-5-yl)(12aS,6aR)-1 -methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
((12aS ,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;
amino(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione;
{[(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]sulfonyl}methylamine;
methylethyl 3-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
methylethyl 3-(4-methoxy-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinolin-9-yl)benzoate;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-10-carbonitrile;
2-((6aS,12aR)-1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((6aS,12aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((12aR,6aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2,4-difluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2,4-dichloro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2-chloro-4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((6aS,12aR)-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3-thiadiazol-4-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-methoxy-7,7-dimethyl-9-(4-methyl(1,2,4-triazol-3-yl))-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
2-((12aS,6aR)-4-methoxy-7,7-dimethyl-2-phenyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
1-bromo-9-ethoxy-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-bromo-4-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-(1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;
1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
amino(1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione;
1-bromo-4-methoxy-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-9-bromo-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aS)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
9-(tert-butyl)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
{[(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]sulfonyl }methylamine;
diethoxy[(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]phosphino-1-one;
[(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]diethoxyphosphino-1-one;
4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenecarbonitrile;
(12aS,6aS)-1-methoxy-7,7-dimethyl-9-[4-(trifluoromethyl)phenyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aS)-1-methoxy-7,7-dimethyl-9-phenyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-9-ethynyl-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
ethyl 4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenesulfonamide;
[4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]methan-1-ol;
(12aS,6aR)-9-(4-fluorophenyl)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-2-methoxybenzene;
1-(4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;
4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS)-4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4-fluoro-9-(2-methoxyphenyl)-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinolin-12-ol;
(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))[(4-methylphenyl)sulfonyl]amine;
4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoic acid;
ethyl 4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzamide;
(12aS,6aR)-9-(4-fluorophenyl)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(2-methyl(1,3-thiazol-4-yl))-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-pyrazol-3-yl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
ethyl 2-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,3-oxazole-4-carboxylate;
((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-4-methoxybenzene;
methyl 3-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]propanoic acid;
(2E)-3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))phenyl]prop-2-enoic acid;
(6aS,12aR)-7-methoxy-13,13-dimethyl-6,13,12a,6a-tetrahydrobenzothiazolo[6,7-b]chromano[3,4-e]pyridine;
(6aS,12aR)-7-methoxy-13,13-dimethyl-6,13,12a,6a-tetrahydro-1H-chromano[3,4-e]indazolo[6,7-b]pyridine;
(6aS,12aR)-7-methoxy-2,13,13-trimethyl-6,13,12a,6a-tetrahydrobenzothiazolo[5,4-b]chromano[3,4-e]pyridine;
(12bS,6aR)-12-methoxy-6,6-dimethyl-6,13,12b,6a-tetrahydrochromano[4,3-b]1,2,5-thiadiazolo[3,4-h]quinoline;
ethyl 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylate;
(6aR,12aS)-6a,7,12,12a-tetrahydro-N-(2-hydroxyethyl)-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic acid;
((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;
((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;
(6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-9-(methylsulfonyl)-6H-chromeno[4,3-b]quinoline; and
(6aR,12aS)-9-(4-fluorophenylsulfonyl)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline.
(6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-N,N,7,7-tetramethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;
2-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-ylsulfonyl)acetic acid;
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone;
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone;
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;
((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;
((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;
((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;
2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic acid;
((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;
((6aS,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;
((6aR,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;
ethyl 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3 -b]quinolin-9-yl)-1H-pyrazole-4-carboxylate;
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-1H-pyrazole-4-carboxylic acid;
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3 -b]quinolin-9-yl)—N,N-dimethyl-1H-pyrazole-4-carboxamide;
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3 -b]quinolin-9-yl)-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);
((6aS,12aS)-4-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3 -b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone);
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);
2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone);
2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone);
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone);
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);
2-((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic acid;
2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3 -b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone);
2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone);
(6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;
(6aR,12aS)-methyl 2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;
(6aS,12aS)-methyl 2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;
(6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-1-methoxy-7,7,12-trimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;
2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetic acid;
(6aR,12aS)-6a,7,12,12a-tetrahydro-12-isopropyl-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetic acid;
ethyl 2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;
ethyl 2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;
(6aR,12aS)-12-benzyl-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline;
(6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate;
(6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-dimethylisoxazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate;
(6aS,12aS)-12-ethyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;
(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-dimethylisoxazol-4-yl)-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline.
(6aR,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline.
diethyl ((6aR, 12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;
(6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;
methyl 3-((6aS,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;
methyl 3-((6aR,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-1 2(12aH)-yl)propanoate;
(6aR,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aR,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7,12-trimethyl-6H-chromeno[4,3-b]quinoline; and
1-((6aS,12aS)-6a,7,12,12a-tetrahydro-2-iodo-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic acid;
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-2-iodo-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic acid;
diethyl ((6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;
diethyl (6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;
diethyl ((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate; and
(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carbonitrile.
DEFINITIONS AND GENERAL PARAMETERS
The term “alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term “substituted alkyl” refers to:
1) an alkyl group as defined above, having from 1 to 7 substituents, for example 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, phosphate, thiocarbonyl, aminosulfinyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, phosphate, quaternary amino, nitro, —SO 3 H, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, SO 2 -aryl and —SO 2 -heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, quaternary amino, cyano, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 1; or 2) an alkyl group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and —N(R a ) v —, where v is 1 or 2 and R a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, quaternary amino, cyano, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or 3) an alkyl group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term “lower alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms. Groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like exemplify this term.
The term “substituted lower alkyl” refers to lower alkyl as defined above having 1 to 7 substituents, for example 1 to 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1-5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-5 atoms as defined above.
The term “alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, for example having from 1 to 20 carbon atoms, for example 1-10 carbon atoms, more for example 1-6 carbon atoms. This term is exemplified by groups such as methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), the propylene isomers (e.g., —CH 2 CH 2 CH 2 — and —CH(CH 3 )CH 2 —) and the like.
The term “lower alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, for example having from 1 to 6 carbon atoms.
The term “substituted alkylene” refers to:
(1) an alkylene group as defined above having from 1 to 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, phosphate, thiocarbonyl, aminosulfinyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, quaternary amino, nitro, —SO 3 H, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, SO 2 -aryl and —SO 2 -heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, quaternary amino, cyano, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or (2) an alkylene group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and —N(R a ) v —, where v is 1 or 2 and R a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocyclyl carbonyl, carboxyester, carboxyamide and sulfonyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, quaternary amino, cyano, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or (3) an alkylene group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above. Examples of substituted alkylenes are chloromethylene (—CH(Cl)—), aminoethylene (—CH(NH 2 )CH 2 —), methylaminoethylene (—CH(NH 2 )CH 2 —), 2-carboxypropylene isomers(—CH 2 CH(CO 2 H)CH 2 —), ethoxyethyl (—CH 2 CH 2 O—CH 2 CH 2 —), ethylmethylaminoethyl (—CH 2 CH 2 N(CH 3 )CH 2 CH 2 —), 1-ethoxy-2-(2-ethoxy-ethoxy)ethane (—CH 2 CH 2 O—CH 2 CH 2 —OCH 2 CH 2 —OCH 2 CH 2 —), and the like.
The term “aralkyl” refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein. “Optionally substituted aralkyl” refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
The term “alkoxy” refers to the group R—O—, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group —Y-Z, in which Y is optionally substituted alkylene and Z is optionally substituted alkenyl, optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein. Preferred alkoxy groups are optionally substituted alkyl-O— and include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.
The term “alkylthio” refers to the group R—S—, where R is as defined for alkoxy.
The term “alkenyl” refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group for example having from 2 to 20 carbon atoms, more for example 2 to 10 carbon atoms and even more for example 2 to 6 carbon atoms and having 1-6, for example 1, double bond (vinyl). Preferred alkenyl groups include ethenyl or vinyl (—CH═CH 2 ), 1-propylene or allyl (—CH 2 CH═CH 2 ), isopropylene, (—C(CH 3 )═CH 2 ), bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is attached to nitrogen, the double bond cannot be alpha to the nitrogen.
The term “lower alkenyl” refers to alkenyl as defined above having from 2 to 6 carbon atoms.
The term “substituted alkenyl” refers to an alkenyl group as defined above having from 1 to 5 substituents, and for example 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, quaternary amino, cyano, halogen, hydroxy, keto, phosphate, thiocarbonyl, aminosulfinyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO 3 H, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, SO 2 -aryl and —SO 2 -heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbon, for example having from 2 to 20 carbon atoms, more for example 2 to 10 carbon atoms and even more for example 2 to 6 carbon atoms and having at least 1 and for example from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl, (—C≡CH), propargyl (or prop-1-yn-3-yl, —CH 2 C≡CH), and the like. In the event that alkynyl is attached to nitrogen, the triple bond cannot be alpha to the nitrogen.
The term “substituted alkynyl” refers to an alkynyl group as defined above having from 1 to 5 substituents, and for example 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, quaternary amino, halogen, hydroxy, keto, phosphate, thiocarbonyl, aminosulfinyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO 3 H, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, SO 2 -aryl and —SO 2 -heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “aminocarbonyl” refers to the group —C(O)NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic or heteroaryl group (e.g., morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “aminothiocarbonyl” or “aminosulfinyl” refers to the group —C(S)NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “aaminosulfonyl” refers to the group —S(O) 2 NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “acylamino” refers to the group —NRC(O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “acyloxy” refers to the groups —O(O)C-alkyl, —O(O)C-cycloalkyl, —O(O)C-aryl, —O(O)C-heteroaryl, and —O(O)C-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, or —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “aryl” refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, for example 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, quaternary amino, halogen, hydroxy, keto, phosphate, thiocarbonyl, aminothiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO 3 H, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO 2 -alkyl, SO 2 -aryl and —SO 2 -heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 to 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “aryloxy” refers to the group aryl- O—wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above. The term “arylthio” refers to the group R—S—, where R is as defined for aryl.
The term “amino” refers to the group —NH 2 .
The term “substituted amino” refers to the group —NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen, or a group —Y-Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “quaternary amino” refers to the group —NRRR where each R is as defined for substituted amino. Any two of the R substituents may be joined to form a heterocyclic group as defined further herein.
The term “carboxyalkyl” refers to the groups —C(O)O-alkyl, —C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, or —S(O) n R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo[2.2.1]heptane, 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl, (2,3,3-trimethylbicyclo[2.2.1]hept-2-yl), or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like.
The term “substituted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 substituents, and for example 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, phosphate, thiocarbonyl, aminothiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, quaternary amino, —SO 3 H, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO 2 -alkyl, SO 2 -aryl and —SO 2 -heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term “halogen” or “halo” refers to fluoro, bromo, chloro, and iodo.
The term “acyl” denotes a group —C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
The term “heteroaryl” refers to an aromatic group (i.e., unsaturated) comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring.
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, for example 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, phosphate, thiocarbonyl, aminothiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, substituted amino, quaternary amino, —SO 3 H, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, SO 2 -aryl and —SO 2 -heteroaryl.
Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazolyl, or benzothienyl).
Examples of heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, tetrazole and the like as well as N-alkoxy-nitrogen containing heteroaryl compounds.
The term “heteroaralkyl” refers to a heteroaryl group covalently linked to an alkylene group, where heteroaryl and alkylene are defined herein. “Optionally substituted heteroaralkyl” refers to an optionally substituted heteroaryl group covalently linked to an optionally substituted alkylene group. Such heteroaralkyl groups are exemplified by 3-pyridylmethyl, quinolin-8-ylethyl, 4-methoxythiazol-2-ylpropyl, and the like.
The term “heteroaryloxy” refers to the group heteroaryl-O—.
The term “heterocyclyl” refers to a monoradical saturated or partially unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, for example 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring wherein said sulfur and phosphorous can be in the following oxidation states —S—, —S(O)—, —S(O)2- and —P—, —P(O)—, and —P(O)2-, respectively.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and for example 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, phosphate, thiocarbonyl, aminosulfinyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, quaternary amino, —SO 3 H, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, SO 2 -aryl and —SO 2 -heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, quaternary amino, —SO 3 H, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include, but are not limited to, tetrahydrofuranyl, morpholino, and piperidinyl.
The term “thiol” refers to the group —SH.
The term “substituted alkylthio” refers to the group —S-substituted alkyl.
The term “heteroarylthiol” refers to the group —S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.
The term “sulfinyl” refers to a group —S(O)R, in which R is alkyl, aryl, or heteroaryl. “Substituted sulfinyl” refers to a group —S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
The term “sulfonyl” refers to a group —S(O) 2 R, in which R is alkyl, aryl, or heteroaryl. “Substituted sulfonyl ” refers to a group —S(O) 2 R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
The term “keto” refers to a group —C(O)—. The term “thiocarbonyl” or “sulfinyl” refers to a group C(S)—. The term “carboxy” refers to a group —C(O)—OH.
“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
The term “compound of Formula I” is intended to encompass the compounds of the invention as disclosed, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, and prodrugs of such compounds. Additionally, the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2 n stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.
“Isomers” are different compounds that have the same molecular formula.
“Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate.
“Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R—S system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified as either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (−) depending on the direction (dextro- or laevorotary) in which they rotate the plane of polarized light at the wavelength of the sodium D line.
The term “therapeutically effective amount” refers to that amount of a compound of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
The term “treatment” or “treating” means any treatment of a disease in a mammal, including:
(i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms.
In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds of Formula I, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
A compound that is an agonist with high intrinsic efficacy evokes the maximal effect of which the biological system is capable. These compounds are known as “full agonists”. They are able to elicit the maximum possible effect without occupying all the receptors, if the efficiency of coupling to the effector process is high. In contrast, “partial agonists” evoke a response but cannot evoke the maximal response of which the biological system is capable. They may have reasonable affinity but low intrinsic efficacy.
The term “therapeutically effective amount” refers to that amount of a compound of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
The term “coronary artery disease” means a chronic disease in which there is arteriosclerosis of the coronary arteries.
The term “atherosclerosis” refers to a form of arteriosclerosis in which deposits of yellowish plaques containing cholesterol, lipoid material, and lipophages are formed within the intima and inner media of large and medium-sized arteries.
The term “treatment” or “treating” means any treatment of a disease in a mammal, including:
(i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms.
Nomenclature
The compounds of the invention are numbered according to the following scheme:
The naming and numbering of the compounds of the invention is illustrated with a representative compound of Formula I:
in which A and D are phenyl, R 1 and R 2 are methyl, R 3 is 3-methoxy, R 4 , R 5 , R 6 , and R 7 are hydrogen, R 8 is 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl, which is named 2-((12aS,6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol. In the above structure, the BC cis ring juncture is indicated as (12aS, 6aR) as drawn, however, it is understood that this also represents (12aR, 6aS) cis compound, since these compounds are racemic. When a specific enantiomer is intended the naming convention will be indicated, for example, as (12aS*, 6aR*).
DETAILED DESCRIPTION OF THE INVENTION
Synthesis of the Compounds of Formula I
The compounds of Formula I in which X is oxygen may be prepared as shown in Reaction Scheme I.
Step 1
In general, the compound of formula (1) is reacted with a compound of formula (1) in a polar solvent, for example N,N-dimethylformamide, in the presence of a base, preferably an inorganic base, for example, potassium carbonate, at room temperature, for about 12-72 hours, preferably about 48 hours. When the reaction is substantially complete, the product of formula (3) is isolated by conventional means and used with no further purification.
Step 2
In general, the compound of formula (3) is reacted with a compound of formula (4) in an inert solvent, for example acetonitrile, in the presence of a catalytic amount of a strong acid, for example, trifluoroacetic acid. The reaction is conducted at room temperature or at about 50-100° C., preferably about 80° C., for about 4-24 hours, preferably about 12 hours. When the reaction is substantially complete, the product of Formula I is isolated using conventional means, for example, chromatography on silica gel or neutral alumina, and may be used without further purification.
Conventional heating is required for the preparation of the compound of Formula in which R 6 is optionally substituted less hindered lower alkyl, —C(O)R 12 , or S(O) 2 R 12 . As before, the compound of formula (3) is generally reacted with the compound of formula (2) in an inert solvent, such as DMF, in the presence of a catalytic amount of a strong acid, for example, trifluoroacetic acid. The reaction is conducted at about 50-100° C., preferably about 90° C., for about 4-48 hours, preferably about 24 hours, and then isolated and purified as discussed above.
Microwave irradiation is useful for the preparation of the compound of Formula I in which R 6 is an optionally substituted hindered substituent, for example a cyclohexyl group. The compounds of formula (2) and (3) are subjected to the same reaction conditions as before, however, the reaction is conducted using microwave irradiation at about 100-220° C., preferably about 180° C., for about 5-60 minutes, preferably about 20 minutes.
Further Substitution on the D Ring
In those instances where R 8 or R 20 is a halogen, preferably bromo, the D ring can be further substituted by carrying out a Suzuki coupling, as shown in Reaction Scheme II.
As shown above, the compound of Formula I in which R 8 is bromo is reacted with an appropriately substituted boronic acid derivative, for example with 4-fluorophenylboronic acid, in an aqueous solvent mixture, for example acetonitrile/aqueous sodium carbonate. The reaction is typically conducted in the presence of a catalyst, for example dichlorobis-(triphenylphosphine) palladium(II), at a temperature of about 150° C., under irradiation in a microwave, for about 10 minutes to about 1 hour. When the reaction is substantially complete, the product of Formula I is isolated by conventional means, for example by partitioning the crude reaction mixture between ethyl acetate/aqueous sodium hydroxide, separating the organic layer, removing the solvent under reduced pressure, followed by chromatography of the residue, preferably preparatory TLC.
In those instances where the R 7 , R 8 , or R 20 moiety has a terminal carboxylic acid group, the D ring can be further substituted to provide an aminocarbonyl linking moiety as shown in Reaction Scheme III.
In Reaction Scheme III, R 8 is depicted as the D ring substituent having the terminal acidic moiety and R 8′ is the portion of R 8 linking the terminal acid group with the D ring. The acidic compound of formula I is reacted with a primary or secondary amine in a polar solvent, for example N,N-dimethylformamide (DMF), in the presence of a coupling reagent, for example, EDCI, and a base, preferably an organic base, for example, triethylamine, at room temperature, for about 12-72 hours, preferably about 48 hours. When the reaction is substantially complete, the product of formula I is isolated by conventional means, for example, aqueous work up and chromatography on silica gel, and may be used without further purification.
It will be appreciated by those of skill in the art that a terminal carbocylic acid group can be easily achieved by hydrolyzing an analogous compound having terminal ethyl ester.
Terminal R 7 , R 8 , or R 20 cyano groups can also be further substituted to provide a tetrazole substituent as shown in Reaction Scheme IV.
In this method, the cyano compound of formula I is reacted with sodium azide and zinc bromide in a polar solvent, for example DMF. The reaction mixture is subjected to microwave irradiation at 220° C. for 30 minutes to an hour and then cooled to room temperature. When the reaction is substantially complete, the product of formula I is isolated by conventional means, for example, aqueous work up and chromatography on silica gel, and may be used without further purification.
Terminal R 7 , R 8 , or R 20 thio groups can also be further substituted to provide a sulfonyl substituent as shown in Reaction Scheme V.
In this method, a cooled (0° C.) solution of the R 8 thio compound of formula I in anhydrous chloroform is reacted with 3-chloroperoxybenzoic acid. The reaction mixture is typically stirred at 0° C. for 5-10 minutes and then the ice bath removed. After about 30 minutes to an hour of stirring at room temperature, the reaction is substantially completed and the product of formula I is isolated by conventional means. Generally isolation and purification may be accomplished by filtering through a layer of dry sodium sulfate (top) and silica gel (bottom), followed aqueous work up and chromatography on silica gel.
It will be appreciated that the above substitutions and modification can be made to the D ring prior to formation of the compound of formula I, i.e., by modification of the compound of formula (4) prior to reaction with the formula (3) compound in Step 2 of Reaction Scheme I. An example of this is presented in Reaction Scheme VI.
Step 1
In general, an acidic variant of the formula (4) compound, compound (4a) is reacted with an amine of formula (5) in a polar solvent, for example DMF, in the presence of a coupling reagent, for example, EDCI, and a base, preferably an organic base, for example, triethylamine, at room temperature, for about 12-72 hours, preferably about 48 hours. When the reaction is substantially complete, the aminocarboxy substituted product of formula (4b), also a formula (4) compound, is isolated by conventional means, for example, aqueous work up and chromatography on silica gel, and may be used without further purification.
Step 2
The compound of formula (4a) is then reacted with a compound of formula (3) in an inert solvent, for example DMF, in the presence of a catalytic amount of a strong acid, for example, trifluoroacetic acid. The reaction is conducted at room temperature or at about 50-100° C., preferably about 80-90° C., or under microwave irradiation at about 150-240° C., preferably about 180° C., for about 10-40 minutes, preferably about 20 minutes. When the reaction is substantially complete, the product of Formula I is isolated using conventional means, for example, chromatography on silica gel or reverse-phase HPLC, and may be used without further purification.
Further Substitution on the A Ring
In those instances where R 3 , R 4 or R 5 is a halogen, preferably iodo or bromo, the A ring can be further substituted by carrying out a Heck reaction, or as shown in Reaction Scheme VII.
As shown above, the compound of Formula I in which R 4 is iodo is reacted with dimethylacrylamide in an inert solvent, for example N,N-dimethylformamide, in the presence of a quarternary base, for example tetrabutylammonium chloride, a catalyst, for example palladium(II) diacetate, and a tertiary base, for example triethylamine. The mixture is heated to a temperature of about 60-100° C., for about 4-24 hours. When the reaction is substantially complete, the product of Formula I is isolated by conventional means.
If desired, the acrylamide derivative can then be reduced to an N,N-dimethyl-propanamide derivative by conventional reduction, for example with a mixture of nickel chloride/sodium borohydride. The reduction is typically carried out in an aqueous solvent, for example methanol/water, at about room temperature.
Alternatively, the A ring can be further substituted by reacting the halogenated compound with a boronic acid derivative of the desired R 4 substituent, or as shown in Reaction Scheme VIII.
As shown above, the compound of Formula I in which R 4 is bromo or iodo is reacted with an appropriately substituted boronic acid derivative, for example with aromatic boronic acid or heterocyclic boronic acid, in an aqueous solvent mixture, for example dimethoxyethane (DME)/aqueous sodium carbonate. The reaction is typically conducted in the presence of a catalyst, for example dichlorobis-(triphenylphosphine) palladium(II), at a temperature of about 150° C., under irradiation in a microwave, for about 10 minutes to about 1 hour. When the reaction is substantially complete, the product of Formula I is isolated by conventional means, for example by filtrating through celite, partitioning the crude reaction mixture between ethyl acetate/aqueous lithium hydroxide, separating the organic layer, removing the solvent under reduced pressure, followed by chromatography of the residue, preferably preparatory TLC or reverse phase HPLC.
UTILITY, TESTING AND ADMINISTRATION
General Utility
The compounds of Formula I stimulate the expression of ABCA1 in mammalian cells, and may thereby increase cholesterol efflux and raise HDL levels in plasma. Thus, the compounds of Formula I are useful for treating conditions treatable by increasing ABCA1 expression including, but not limited to, coronary artery disease, dyslipidiemia and metabolic syndrome and may also be useful in treating other conditions related to high cholesterol/low HDL levels in mammals.
Testing
Activity testing is conducted as described in those patents and patent applications referenced above, and in the Examples below, and by methods apparent to one skilled in the art.
Pharmaceutical Compositions
The compounds of Formula I are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds of Formula I, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The compounds of Formula I may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17 th Ed. (1985) and “Modern Pharmaceutics”, Marcel Dekker, Inc. 3 rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).
Administration
The compounds of Formula I may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
One mode for administration is parental, particularly by injection. The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
Sterile injectable solutions are prepared by incorporating the compound of Formula I in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Oral administration is another route for administration of the compounds of Formula I. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound of Formula I, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, in can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
The compositions are preferably formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds of Formula I are effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 10 mg to 2 g of a compound of Formula I, more preferably from 10 to 700 mg, and for parenteral administration, preferably from 10 to 700 mg of a compound of Formula I, more preferably about 50-200 mg. It will be understood, however, that the amount of the compound of Formula I actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
EXAMPLE 1
Preparation of a Compound of Formula (3)
A. Preparation of a Compound of Formula (3) in which A is Phenyl, R 1 and R 2 are Methyl, R 3 is 2-Methoxy R 4 and R 5 are Hydrogen, and X is Oxygen
To a solution of 2-hydroxy-5-methoxybenzaldehyde (7.6 g, 50 mmol) in dry N,N-dimethylformamide (100 mL) was added potassium carbonate (10.4 g), followed by 1-bromo-3-methylbut-2-ene (10.0 g, 67 mmol). The mixture was stirred at room temperature for 48 hours and ethyl acetate added. Sufficient 1M hydrochloric acid was cautiously added to neutralize the base, and the organic layer was washed with water three times, followed by brine, and dried over magnesium sulfate. The mixture was filtered, and solvent removed from the filtrate under reduced pressure, to provide 5-methoxy-2-(3 -methylbut-2-enyloxy)benzaldehyde.
1 H NMR (400 MHz, CDCl 3 ) δ 1.73(s, 3H), 1.79(s, 3H), 3.8(s, 3H), 4.6(d, J=6.6 Hz, 2H), 5.48(m, 1H), 6.96(d, J=9.3 Hz, 1H), 7.12(dd, J=9.0, 3.5 Hz, 1H), 7.52(d, J=3.5 Hz, 1H), 10.45(s, 1H)
B. Preparation of a Compound of Formula (3), varying R 1 , R 2 , R 3 , and R 4
Similarly, following the procedure of 1A above, but replacing 2-hydroxy-5-methoxybenzaldehyde with other formula (1) compounds or replacing 1-bromo-3-methylbut-2-ene with other formula (2) compounds, the following compounds of formula (3) were prepared:
2-(3-methylbut-2-enyloxy)benzaldehyde;
5-bromo-2-(3-methylbut-2-enyloxy)benzaldehyde;
3-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde;
6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde;
3-ethoxy-2-(3-methylbut-2-enyloxy)benzaldehyde;
3-methyl-2-(3-methylbut-2-enyloxy)benzaldehyde;
4-carboxy-2-(3-methylbut-2-enyloxy)benzaldehyde;
3-fluoro-2-(3-methylbut-2-enyloxy)benzaldehyde;
5-trifluoromethyloxy-2-(3-methylbut-2-enyloxy)benzaldehyde;
3-methoxy-5-bromo-2-(3-methylbut-2-enyloxy)benzaldehyde;
4-methoxy-6-bromo-2-(3-methylbut-2-enyloxy)benzaldehyde;
3-methoxy-5-chloro-2-(3-methylbut-2-enyloxy)benzaldehyde;
3,5-difluoro-2-(3-methylbut-2-enyloxy)benzaldehyde;
3,5-dichloro-2-(3-methylbut-2-enyloxy)benzaldehyde;
2,3-bis(3-methylbut-2-enyloxy)benzaldehyde;
3-methylbut-2-enyl 3-formyl-4-(3-methylbut-2-enyloxy)benzoate;
3-methylbut-2-enyl 4-formyl-3-(3-methylbut-2-enyloxy)benzoate;
2-(cinnamyloxy)-6-methoxybenzaldehyde; and
2-(3-methylbut-2-enyloxy)-3,6-dimethylbenzaldehyde.
C. Preparation of a Compound of Formula (3), varying R 1 , R 2 , R 3 , R 4 , R 5 , and X
Similarly, following the procedure of 1A above, but replacing 2-hydroxy-5-methoxybenzaldehyde with other formula (1) compounds or replacing 1 -bromo-3-methylbut-2-ene with other formula (2) compounds, the following compounds of formula (3) are prepared.
5-methoxy-2-(3-methylbut-2-enylthio)benzaldehyde;
2-(3-methylbut-2-enylthio)benzaldehyde
5-bromo-2-(3-methylbut-2-enylthio)benzaldehyde;
3-methoxy-2-(3-methylbut-2-enylthio)benzaldehyde;
6-methoxy-2-(3-methylbut-2-enylthio)benzaldehyde;
3-ethoxy-2-(3-methylbut-2-enylthio)benzaldehyde;
3-methyl-2-(3-methylbut-2-enylthio)benzaldehyde;
4-carboxy-2-(3-methylbut-2-enylthio)benzaldehyde;
3-fluoro-2-(3-methylbut-2-enylthio)benzaldehyde;
5-trifluoromethyloxy-2-(3-methylbut-2-enylthio)benzaldehyde;
3-methoxy-5-bromo-2-(3-methylbut-2-enylthio)benzaldehyde;
4-methoxy-6-bromo-2-(3-methylbut-2-enylthio)benzaldehyde;
3-methoxy-5-chloro-2-(3-methylbut-2-enylthio)benzaldehyde;
3,5-difluoro-2-(3-methylbut-2-enylthio)benzaldehyde;
3,5-dichloro-2-(3-methylbut-2-enylthio)benzaldehyde;
2,3 -bis(3-methylbut-2-enylthio)benzaldehyde;
3-methylbut-2-enyl 3-formyl-4-(3-methylbut-2-enylthio)benzoate; and
3-methylbut-2-enyl 4-formyl-3-(3-methylbut-2-enylthio)benzoate.
D. Preparation of a Compound of Formula (3), varying A, R 1 , R 2 , R 3 , R 4 , R 5 , and X
Similarly, following the procedure of 1A above, but replacing 2-hydroxy-5-methoxybenzaldehyde with other formula (1) compounds or replacing 1-bromo-3-methylbut-2-ene with other formula (2) compounds, other compounds of formula (3) are prepared.
EXAMPLE 2
Preparation of a Compound of Formula (3)
A. Preparation of a Compound of Formula (3) in which A is Phenyl, R 1 is Methyl, R 2 is 3-Methylbut-2-enyl, R 3 is 2-Methoxy, R 4 and R 5 are Hydrogen, and X is Oxygen
To a solution of 2-hydroxy-6-methoxybenzaldehyde (4.72 g, 30.43 mmol) in dry DMF (50 ml) was added geranyl bromide (7.5 g, 33.50 mmol) followed by solid potassium carbonate (5.5 g, 39.86 mmol). The mixture was stirred at room temperature for 48 h. The suspension was filtered through a layer of dry sodium sulfate (top) and silica gel (bottom), washed with 200 ml ethyl acetate and decanted into a separatory funnel. The mixture was washed sequentially with aqueous ammonium chloride, water (twice), brine, and the organic phase was dried over Na 2 SO4. The solution was concentrated in vacuo on a rotovap. The brown gel material was then purified by chromatography via silica gel using 8:2 hexanes:ethyl acetate eluent to provide 2-((E)-3,7-dimethylocta-2,6-dienyloxy)-6-methoxybenzaldehyde as pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 10.56 (s, 1H ); 7.47 (t, aromatic 1H, J=8.60 Hz); 6.604 (d, 1H, J=8.22 Hz); 6.59 (d, 1H, J=8.22 Hz); 5.51 (td, 1H, J=6.65 and 1.17 Hz); 5.11 (m, 1H); 4.67 (d, 2H, J=6.65 Hz); 3.95 (s, 3H); 2.16 (m, 4H); 1.50-1.80 (s, 9H).
B. Preparation of a Compound of Formula (3), varying R 1 , R 2 , R 3 and R 4
Similarly, following the procedure of 2A above, but replacing 2-hydroxy-5-methoxybenzaldehyde with other formula (1) compounds or replacing geranyl bromide with other formula (2) compounds, other compounds of formula (3) are prepared.
EXAMPLE 3
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which A and D are Phenyl, R 1 and R 2 are Methyl, R 3 is 3-Methoxy, R 4 , R 5 , R 6 , R 7 and R 8 are Hydrogen, R 20 is 1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen
A solution of 5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde (1.1 g, 5 mmol), 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.3 g, 5 mmol) and a catalytic amount of trifluoroacetic acid in acetonitrile (15 ml) was heated at 80° C. for 12 hours. After cooling, the solvent was removed under reduced pressure, and the residue chromatographed on silica gel (150 g), eluting with 30% ethyl acetate/hexanes, providing 1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol (as a 1:1 mixture of cis/trans isomers).
B. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 3A above, but replacing 5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3) compounds or replacing 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol with other compounds of formula (4), the following compounds of Formula I were prepared:
2-(2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((6aS,12aR)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3 -b]quinolin-9-yl)acetic acid;
2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
methyl 2-bromo-1 0-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylate;
1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
2-[7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-[(12aS,6aS)-7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;
3-methylbut-2-enyl (6aS, 12aR)-9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;
3-methylbut-2-enyl 9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;
3-methylbut-2-enyl 7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;
3-methylbut-2-enyl 7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate;
7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylic acid;
3 -methylbut-2-enyl 9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate;
7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylic acid;
9-(dihydroxyboramethyl)-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinoline-3-carboxylic acid;
1,1,1,3,3,3-hexafluoro-2-(4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;
4-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;
2-(4-ethoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
2-[7,7-dimethyl-4-(3-methylbut-2-enyloxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)acetic acid;
3-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic acid;
3-((12aR,6aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic acid;
4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS)-4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
2-((6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
(6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4-ethoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-(4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;
1-(1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3 -b]quinolin-9-yl)ethan-1-one;
1-methoxy-7,7-dimethyl-9-(trifluoromethy;1)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
(6aS,12aR)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aS)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(6aS,12aR)-9-fluoro-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylic acid;
4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
1,1,1,3,3,3-hexafluoro-2-(4-fluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
((6aS,12aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-9-fluoro-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-9-ethoxy-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylic acid;
10-(1H-1,2,3,4-tetraazol-5-yl)(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;
amino(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione;
{[(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]sulfonyl}methylamine;
methylethyl 3-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
methylethyl 3-(4-methoxy-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinolin-9-yl)benzoate;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-10-carbonitrile;
2-((6aS,12aR)-1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((6aS,12aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((12aR,6aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2,4-difluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2,4-dichloro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2-chloro-4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3 -hexafluoropropan-2-ol;
2-((6aS,12aR)-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3 -b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3-thiadiazol-4-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; and
1-methoxy-7,7-dimethyl-9-(4-methyl(1,2,4-triazol-3-yl))-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline.
9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
2-((12aS,6aR)-4-methoxy-7,7-dimethyl-2-phenyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
1-bromo-9-ethoxy-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-bromo-4-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-(1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;
1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
amino(1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione;
1-bromo-4-methoxy-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-9-bromo-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aS)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
9-(tert-butyl)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
{[(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]sulfonyl}methylamine;
diethoxy[(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]phosphino-1-one;
[(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]diethoxyphosphino-1-one;
1-(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-2-methoxybenzene;
1-(4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;
4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS)-4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4-fluoro-9-(2-methoxyphenyl)-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinolin-12-ol;
(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))[(4-methylphenyl)sulfonyl]amine;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(2-methyl(1,3-thiazol-4-yl))-7,12,12a,6a-tetrahydrochromano [4,3 -b]quinoline;
12aS,6aR)-1-methoxy-7,7-dimethyl-9-pyrazol-3-yl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
ethyl 2-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,3-oxazole-4-carboxylate;
(6aS,12aR)-7-methoxy-13,13-dimethyl-6,13,12a,6a-tetrahydrobenzothiazolo[6,7-b]chromano[3,4-e]pyridine;
(6aS,12aR)-7-methoxy-13,13 -dimethyl-6,13,12a,6a-tetrahydro-1H-chromano[3,4-e]indazolo[6,7-b]pyridine;
(6aS,12aR)-7-methoxy-2,13,13-trimethyl-6,13,12a,6a-tetrahydrobenzothiazolo[5,4-b]chromano[3,4-e]pyridine; and
(12bS,6aR)-12-methoxy-6,6-dimethyl-6,13,12b,6a-tetrahydrochromano[4,3-b]1,2,5-thiadiazolo[3,4-h]quinoline
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-methylthio-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7-phenyl(7,12,12a,6a-tetrahydrochromano[4,3 -b]quinolin-9-yl))propan-2-ol;
((7S,12aS,6aR)-1-methoxy-7-phenyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))—N,N-dimethylcarboxamide;
(7S,12aS,6aR)-1-methoxy-9-morpholin-4-yl-7-phenyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carbonitrile;
(12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4-{[(12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-7,12,12a,6a-tetrahydrochromano[4,3 -b]quinolin-9-yl]methyl }-1,4-thiazaperhydroine-1,1-dione; and
methyl (12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylate.
ethyl 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3 -b]quinolin-9-yl)-1H-pyrazole-4-carboxylate;
ethyl 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3 -b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylate;
(6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;
(6aR,12aS)-methyl 2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;
(6aS,12aS)-methyl 2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;
(6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;
diethyl ((6aR, 12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;
(6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;
diethyl ((6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3 -b]quinolin-9-yl)methylphosphonate;
(6aR,12aS)-6a,7,12,12a-tetrahydro-N-(2-hydroxyethyl)-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;
((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;
((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;
(6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-N,N,7,7-tetramethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone;
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone;
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;
((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1 -dione-1,4-thiazaperhydroin-yl)methanone;
((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1 -dione-1,4-thiazaperhydroin-yl)methanone;
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1 -dione-1,4-thiazaperhydroin-yl)methanone;
((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;
((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;
((6aS,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;
((6aR,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone; and
((6aS,12aS)-4-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone.
C. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 3A above, but replacing 5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3) compounds or replacing 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol with other compounds of formula (4) or (4b), the following compounds of Formula I are prepared:
2-(2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol
2-((6aS,12aR)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-9-carboxamide:
1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;
1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;
2-[7,7-dimethyl-2-(trifluoromethoxy)( 7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-[(12aS,6aS)-7,7-dimethyl-2-(trifluoromethoxy)( 7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;
3-methylbut-2-enyl 7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl] -7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-3 -carboxylate
3-methylbut-2-enyl 7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[3,4-e]quinolino[3,2-c]thiane-2-carboxylate
7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-3-carboxylic acid
1,1,1,3,3,3-hexafluoro-2-(4,7,7-trimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;
4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane
4-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)-1,4-thiazaperhydroine-1,1 -dione;
4-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)-1,4-thiazaperhydroine-1,1-dione;
2-(4-ethoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-9-carboxamide
1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;
2-[7,7-dimethyl-4-(3-methylbut-2-enyloxy)( 7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)acetic acid;
4,7,7-trimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-9-carboxamide;
4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-9-carboxamide;
4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
4,7,7-trimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane
(12aS)-4,7,7-trimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane
1,1,1,3,3,3 -hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;
2-((6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
(6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
(12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
4-ethoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
1-(4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)ethan-1-one;
1-(1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)ethan-1-one;
1-methoxy-7,7-dimethyl-9-(trifluoromethy;l)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane-9-carboxamide
(6aS,12aR)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
(12aS,6aS)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
(6aS,12aR)-9-fluoro-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-9-carboxamide
1,1,1,3,3,3 -hexafluoro-2-(4-fluoro-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;
4-methoxy-7,7-dimethyl-9-(methylethoxy)-7,12-dihydro-6H-benzo[e]quinolino[3,2-c]thiin
9-ethoxy-4-methoxy-7,7-dimethyl-7,12-dihydro-6H-benzo[e]quinolino[3,2-c]thiin
((6aS,12aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl oxy))trifluoromethane;
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
(12aS,6aR)-9-fluoro-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
(12aS,6aR)-9-ethoxy-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiin-9-carboxylic acid
10-(1H-1,2,3,4-tetraazol-5-yl)(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl oxy))trifluoromethane;
amino(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))methane-1-thione;
{[(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))methyl]sulfonyl}methylamine;
methylethyl 3-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)benzoate;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiin-10-carbonitrile
2-((6aS,12aR)-1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((6aS,12aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((12aR,6aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2,4-difluoro-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2,4-dichloro-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-(2-chloro-4,7,7-trimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2-((6aS,12aR)-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)-1,4-thiazaperhydroine-1,1-dione;
4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3-thiadiazol-4-yl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane; and
1-methoxy-7,7-dimethyl-9-(4-methyl(1,2,4-triazol-3-yl))-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane.
D. Preparation of a Compound of Formula I, varying A, D, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 3A above, but replacing 5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3) compounds or replacing 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol with other compounds of formula (4) or (4b), other compounds of Formula I are prepared.
EXAMPLE 4
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which A and D are Phenyl, R 1 and R 2 are Methyl, R 3 is 2-Methoxy, R 4 , R 5 , R 6 , R 7 and R 8 are Hydrogen, R 20 is —C(O)NH(CH 2 ) 2 OH, and X is Oxygen
As shown above, to a solution of 6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde (220 mg, 1.0 mmol) and 4-(1,3-oxazolin-2-yl)phenylamine (162 mg, 1.0 mmol) in anhydrous DMF (10 ml) was added trifluoroacetic acid (57 mg, 0.5 mmol). The reaction mixture was stirred at 80° C. for about 2 hours when it was substantially done. After cooling, this reaction mixture was taken up with ethyl acetate (30 ml) and decanted into a separatory funnel. The organic phase was washed sequentially with water (30 ml), saturated ammonium chloride (30 ml), brine, and dried over Na 2 SO4. The solution was concentrated in vacuo on a rotovap. The crude mixture was then purified by reverse phase HPLC using a gradient eluent (2.5 to 97.5% acetonitrile in water) to provide the desired material ((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-N-(2-hydroxyethyl)carboxamide as white solid.
1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (d, 1 H, J=1.75 Hz); 7.40 (dd, 1 H, J=9.20, 2.10 Hz); 7.21 (t, 1 H, J=8.22 Hz); 6.55 (m, 2 H); 6.48 (m, 1 H); 6.38 (d, 1 H, J=8.61 Hz ); 4.89 (d, 1 H, J=3.52 Hz); 4.69 (s, 1 H); 4.24 (ddd, 1 H, J=10.55, 3.52, 1.17 Hz); 3.95 (s, 3 H); 3.85 (m, 2 H); 3.63 (m, 2 H); 3.57 (dd, 1 H, J=12.13, 10.96 Hz,); 1.99 (m, 1 H); 1.39-1.56 (s, 6 H). MS mz (M+H): 383.06.
B. Preparation of a Compound of Formula I, varying R 20
Similarly, following the procedure of 4A above, but replacing 6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3) compounds or replacing 4-(1,3-oxazolin-2-yl)phenylamine with other compounds of formula (4) or (4b), other compounds of Formula I are prepared.
EXAMPLE 5
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which A and D are Phenyl, R 1 , R 2 , and R 6 are Methyl, R 3 is 2-Methoxy, R 4 , R 5 , R 7 and R 8 are Hydrogen, R 20 is —C(O)OCH 3 , and X is Oxygen
To a solution of compound 6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde (220 mg, 1.0 mmol) and methyl 4-(methylamino)benzoate (165 mg, 1.0 mmol) in anhydrous DMF (10 ml) was added trifluoroacetic acid (57 mg, 0.5 mmol). The reaction mixture was stirred at 90° C. for about 24 hours when it was substantially done. After cooling, this reaction mixture was taken up with ethyl acetate (30 ml) and decanted into a separatory funnel. The organic phase was washed sequentially with water (30 ml), saturated aqueous sodium bicarbonate (30 ml), ammonium chloride (30 ml), brine, and dried over Na 2 SO4. The solution was concentrated in vacuo on a rotovap. The resulting yellow gel was then purified by chromatography via silica gel using 8:2 hexanes:ethyl acetate eluent to provide 320 mg (87%) of the desired diastereomers methyl (12aS,6aR)-1-methoxy-7,7,12-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylate and methyl (12aS,6aS)-1-methoxy-7,7,12-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylate as pale yellow solid (5.5/1 cis/trans). Reverse phase HPLC using a gradient eluent (2.5 to 97.5% acetonitrile in water) provided the desired product methyl (12aS,6aR)-1-methoxy-7,7,12-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylate as off-white solid.
1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (d, 1 H, J=1.96 Hz); 7.82 (dd, 1 H, J=8.61, 1.96 Hz); 7.25 (t, 1 H, J=8.22 Hz); 6.64 (d, 1 H, J=9.00 Hz); 6.54 (m, 2 H); 4.95 (s, 1 H); 4.30 (dd, 1 H, J=10.56, 3.13 Hz); 3.91 (s, 3 H); 3.87 (m, 1 H); 2.84 (s, 1 H); 2.00 (m, 1 H); 1.41-1.50 (s, 6 H). MS mz (M+H): 367.96.
B. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 5A above, but replacing 5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3) compounds or replacing methyl 4-(methylamino)benzoate with other compounds of formula (4) or (4b), the following compounds of Formula I were prepared:
2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetic acid;
2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetic acid;
ethyl 2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;
ethyl 2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;
(6aS,12aS)-12-benzyl-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aR,12aS)-12-benzyl-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aR,12aS)-12-ethyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-12-ethyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
methyl 3-((6aS,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;
methyl 3-((6aR,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;
(6aR,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aR,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;
(6aS,12aS)-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7,12-trimethyl-6H-chromeno[4,3-b]quinoline; and
(6aS,12aS)-3-(benzyloxy)-6a,7,12,12a-tetrahydro-9-methoxy-7,7,12-trimethyl-6H-chromeno[4,3-b]quinoline.
C. Preparation of a Compound of Formula I, varying A, D, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 5A above, but replacing 5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3) compounds or replacing methyl 4-(methylamino)benzoate with other compounds of formula (4), other compounds of Formula I are prepared.
EXAMPLE 6
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which A and D are Phenyl, R 1 and R 2 are Methyl, R 6 is Cyclohexyl, R 3 is 2-Methoxy, R 4 , R 5 , R 7 , R 8 , and R 20 are Hydrogen, and X is Oxygen
As shown above, to a 3 ml Biotage reaction vial equipped with a stir bar was placed 6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde (220 mg, 1.0 mmol), cyclohexylphenylamine (167 mg, 0.95 mmol) in anhydrous DMF (2 ml) and trifluoroacetic acid (57 mg, 0.5 mmol). The reaction vial was capped, subjected to Personal Chemistry microwave irradiation at 180° C. for 30 minutes. After cooling, this reaction mixture was taken up with ethyl acetate (30 ml) and decanted into a separatory funnel. The organic phase was washed sequentially with water (30 ml), saturated aqueous sodium bicarbonate (30 ml), ammonium chloride (30 ml), brine, and dried over Na 2 SO 4 . The solution was concentrated in vacuo on a rotovap. The resulting yellow gel was then purified by chromatography via silica gel using dichloromethane eluent to provide the desired cis-isomer (12aS,6aR)-12-cyclohexyl-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline and trans-isomer.
1 H NMR for cis-isomer (12aS,6aR)-12-cyclohexyl-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline (400 MHz, CDCl 3 ) δ 7.15-7.20 (m, 2 H); 7.08 (m, 1 H); 6.63 (m, 2 H); 6.49 (d, 1 H, J=8.2Hz); 6.45 (dd, 1 H, J=8.2, 0.88 Hz); 4.95 (d, 1 H, J=1.1 Hz); 4.24 (m, 1 H); 3.97 (dd, 1 H, J=12.5, 10.6 Hz); 3.86 (s, 3 H); 3.25 (m, 1 H); 2.98 (m, 1 H); 1.91 (m, 1 H); 1.50-1.60 (m, 5 H); 1.36-1.38 (m, 7 H); 0.70 (t, 3 H, J=7.4 Hz). MS mz (M+H): 377.9.
B. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 6A above, but replacing 6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3) compounds or replacing cyclohexylphenylamine with other compounds of formula (4), the following compounds of Formula I were prepared:
(6aR,12aS)-6a,7,12,12a-tetrahydro-12-isopropyl-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline; and (6aS,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline.
C. Preparation of a Compound of Formula I, varying A, D, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 6A above, but replacing 6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3) compounds or replacing cyclohexylphenylamine with other compounds of formula (4), other compounds of Formula I are prepared.
EXAMPLE 7
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R 1 and R 2 are Methyl, R 3 is 5-Methoxy, R 4 , R 5 , R 6 , R 7 and R 8 are Hydrogen, R 20 is 1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen
To a 5 ml Biotage vial equipped with a stir bar was added (12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline (37 mg, 0.1 mmol), 4-fluorophenyl-boronic acid (17 mg, 0.12 mmol), 125 μl of 2N aqueous sodium carbonate solution, and acetonitrile/water (1.5 ml/1 ml). The mixture was stirred at room temperature for 2 minutes under nitrogen, then dichloro bis(triphenylphosphine)palladium (II) (3.5 mg, 0.005 mmol) was added, and the vial sealed. The vial was subjected to irradiation in a chemistry microwave (Emrys Optimizer) for 15 minutes at a temperature of 150° C., then cooled, filtered through celite, and washed with ethyl acetate (50 ml). The filtrate was washed with 0.5N aqueous sodium hydroxide (30 ml), followed by saturated ammonium chloride, then brine, and dried over sodium sulfate. After removal of the solvent under reduced pressure the residue was dissolved in acetone (50 ml) then subjected to preparative thin layer chromatography, eluting with ethyl acetate/hexanes (9:1). Evaporation of the solvent provided (12aS,6aR)-9-(4-fluorophenyl)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline. MS 390.06 (M+H).
B. Preparation of a Compound of Formula I, varing R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 7A above, but replacing (12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline with other Formula I compounds or replacing 4-fluorophenyl-boronic acid with other boronic acid derivates, the following compounds of Formula I were prepared:
4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3 -b]quinolin-9-yl)benzenecarbonitrile;
(12aS,6aS)-1-methoxy-7,7-dimethyl-9-[4-(trifluoromethyl)phenyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aS)-1-methoxy-7,7-dimethyl-9-phenyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
(12aS,6aR)-9-ethynyl-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
ethyl 4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenesulfonamide;
[4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]methan-1-ol;
4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoic acid;
ethyl 4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzamide;
(12aS,6aR)-9-(4-fluorophenyl)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
1-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-4-methoxybenzene;
methyl 3-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]propanoic acid; and
(2E)-3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))phenyl]prop-2-enoic acid.
C. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 7A above, but replacing (12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline with other Formula I compounds or replacing 4-fluorophenyl-boronic acid with other boronic acid derivates, other compounds of Formula I are prepared.
EXAMPLE 8
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R 1 and R 2 are Methyl, R 3 is 5-Methoxy, R 4 , R 5 , R 6 , R 7 and R 8 are Hydrogen R 20 is 1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen
2.68 g of ethyl 1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylate, prepared as described in Example 3, was in a solution of 30 mL THF, 30 mL of methanol, 30 mL of H 2 O. To this solution was added 1.3 g of LiOH.H 2 O. The reaction was stirred at room temperature over the weekend. The solvent was then removed and solution titrated so provide a solid that was collected by filtration and washed to give the product, 1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylic acid.
B. Preparation of a Compound of Formula I in which R 1 and R 2 are Methyl, R 3 is 5-Methoxy, R 4 , R 5 , R 6 , R 7 and R 8 are Hydrogen, R 20 is 1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen
Similarly, following the procedure of 8A above, but replacing ethyl 1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylate with other Formula I compounds, the following compounds of Formula I were prepared:
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic acid; acid 2-((6aR,12aS)-1-fluoro-6a,7, 12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic acid.
C. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 8A above, but replacing ethyl 1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylate with other Formula I compounds, other compounds of Formula I are prepared.
EXAMPLE 9
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R 1 and R 2 are Methyl, R 3 is 5-Methoxy, R 4 , R 5 , R 6 , R 7 and R 8 are Hydrogen, R 20 is 1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen
70 mg of the 1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylic acid prepared in Example 8A was placed in 5 ml of dichloromethane along with the following:
EDC.HCl 39.7 mg; 1-hydroxybenzotriazole.H 2 O 31.7 mg; and Me 2 NH.HCl 16.9 mg.
The reaction mixture was stirred at room temperature overnight and then worked up with 1N HCl, died over Na 2 SO 4 , and then concentrated to yield the product, [1-((12aS,6aR)-1-methoxy-7,7-dimethyl (7,12,12a,6a-tetrahydrochromano[4,3 -b]quinolin-9-yl))pyrazol-4-yl]—N,N-dimethylcarboxamide, as a yellow oil. 1H NMR confirmed the final product was as intended.
B. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 20 , and X
Similarly, following the procedure of 9A above, but replacing 1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylic acid with other Formula I compounds or replacing dimethyl amine with other amine derivates, the following compounds of Formula I were prepared:
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone);
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);
2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone);
2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone);
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone);
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);
2-((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic acid;
2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone); and
2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3 -b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone.
C. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 9A above, but replacing 1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylic acid with other Formula I compounds or replacing dimethyl amine with other amine derivates, other compounds of Formula I are prepared.
EXAMPLE 10
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which A and D are Phenyl, R 1 and R 2 are Methyl, R 3 is 2-Methoxy, R 4 , R 5 , R 6 , R 7 and R 8 are Hydrogen, R 20 is 2-Nitrophenyl, and X is Oxygen
To a 5 ml Biotage microwave reaction vial was placed a stir bar, 3-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenecarbonitrile (40 mg, 0.1 mmol), sodium azide (20 mg, 0.3 mmol), zinc bromide (46 mg, 0.2 mmol) and DMF (2.0 ml). The reaction mixture was capped and subjected for irradiation at 220° C. for 1 h in a Personal Chemistry microwave. The reaction mixture was cooled to room temperature, and 3 ml water added. It was then filtered through a layer of celite, washed with ethyl acetate (3×10 ml), combined organic phase was washed with saturated aqueous sodium bicarbonate (30 ml), ammonium chloride (30 ml), and brine (30 ml), dried over anhydrous sodium sulfate, concentrated to afford pale yellow solid 9-(3-(2H-1,2,3,4-tetraazol-5-yl)phenyl)(12aS,6aR)-l-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline. MS: m/z (M+H) 439.9.
B. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 10A above, but replacing 3-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenecarbonitrile with other Formula I compounds, other compounds of Formula I are prepared.
EXAMPLE 11
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which A and D are Phenyl, R 1 and R2 are Methyl, R 3 is 2-Methoxy, R 4 , R 5 , R 6 , R 7 and R 8 are Hydrogen, R 20 is 2-Nitrophenyl, and X is Oxygen
As shown above, to a cooled (0° C.) solution of (12aS,6aR)-1-methoxy-7,7-dimethyl-9-methylthio-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline (106 mg, 0.31 mmol) in anhydrous chloroform (5 ml) was added 3-chloroperoxybenzoic acid (208 mg, 1.2 mmol). The resulting reaction mixture was stirred at 0° C. for 5 minutes and the ice bath was then removed. After about 30 minutes of stir at room temperature, the reaction was substantially done. The mixture was filtered through a layer of dry sodium sulfate (top) and silica gel (bottom), washed with 50 ml ethyl acetate and decanted into a separatory funnel. The organic phase was washed sequentially with aqueous lithium hydroxide (1N, 5 ml), saturated ammonium chloride (3×10 ml), water, brine, and dried over Na 2 SO4. The solution was concentrated in vacuo on a rotovap. The mostly pure yellow solid was then purified by chromatography via silica gel using 5% MeOH/CHCl 3 eluent to provide (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylsulfonyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline as a white solid.
1 H NMR (400 MHz, CDCl 3 ) δ 7.63 (d, 1 H, J=1.96 Hz ); 7.49 (dd, 1H, J=8.41, 2.35 Hz); 7.19 (t, 1 H, J=8.22 Hz); 6.53 (m, 2H); 6.43 (d, 1H, J=8.61 Hz); 4.86 (m, 1H); 4.73 (m, 1H); 4.22 (ddd, 1H, J=10.76, 3.52, 1.56 Hz); 3.93 (s, 3H); 3.49 (dd, 1H, J=12.13, 10.56Hz); 3.01 (s, 3H); 2.00 (m, 1H); 1.53-1.61 (s, 6H). MS mz (M+H): 374.1.
B. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 11A above, the following sulfoxide compounds of Formula I were prepared:
2-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-ylsulfonyl)acetic acid; and (6aR,12aS)-9-(4-fluorophenylsulfonyl)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline.
C. Preparation of a Compound of Formula I, varying A, D, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 11A above, other sulfoxide compounds of Formula I are prepared.
EXAMPLE 12
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R 1 and R 2 are Methyl, R 3 is 3-Dimethylacrylamide, R 4 , R 5 , R 6 , R 7 and R 8 are Hydrogen, R 20 is 1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen
To a solution of 1,1,1,3,3,3-hexafluoro-2-(2-iodo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol (2.2 g, 3.95 mmol) in dry N,N-dimethylformamide (5 ml) was added tetrabutylammonium chloride (660 mg, 4 mmols), dimethylacrylamide (309 μl), triethylamine (1.4 ml, 10 mmol), followed by palladium diacetate (87 mg, 0.39 mmol). The mixture was heated at 80° C. for 12 hours, cooled, and ethyl acetate was added. The organic layer was washed with 1M aqueous hydrochloric acid, water, saturated sodium bicarbonate, brine, and the organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate, to yield (2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}—N,N-dimethylprop-2-enamide. The NMR was satisfactory for the proposed structure.
B. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 12A above, but replacing 4 dimethylacrylamide with methyl prop-2-enoate, methyl (2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7, 12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}prop-2-enoate was prepared.
C. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 12A above, but replacing 1,1,1,3,3,3-hexafluoro-2-(2-iodo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol with other Formula I compounds or replacing dimethylacrylamide with other compounds having a terminal carbon-carbon double bond, other compounds of Formula I are prepared.
EXAMPLE 13
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R 1 and R 2 are Methyl, R 3 is 3-Dimethylpropanamide, R 4 , R 5 , R 6 , R 7 and R 8 are Hydrogen, R 20 is 1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen
To a solution of(2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}—N,N-dimethylprop-2-enamide (100 mg, 0.19 mmol) in methanol/water (6 ml of 5/1) at room temperature was added nickel chloride hexahydrate (227 mg, 1.0 mmol), followed by sodium borohydride (18 mg, 0.5 mmol) in portions. The mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate, followed by water, and finally brine. The organic layer was dried over magnesium sulfate, and solvent removed under reduced pressure. The residue was dissolved in ethyl acetate and passed through a portion of silica gel, to provide 3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}—N,N-dimethylpropanamide. NMR satisfactory.
B. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 13A above, but replacing
(2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}—N,N-dimethylprop-2-enamide
with
methyl (2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}prop-2-enoate, methyl 3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl}propanoate; was prepared.
C. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 13A above, but replacing
(2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}—N,N-dimethylprop-2-enamide
with other Formula I compounds having an unsaturated carbon-carbon double bond, other compounds of Formula I are prepared.
EXAMPLE 14
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R 1 and R 2 are Methyl, R 4 is Pyrazol-4-yl, R 3 is 5-Methoxy, R 5 , R 6 , R 7 and R 8 are Hydrogen, R 20 is Oxazol-5-yl, and X is Oxygen
As shown above, to a 3 ml Biotage reaction vial equipped with a stir bar was placed compound (12aS,6aR)-2-bromo-4-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline (22 mg, 0.05 mmol), 4,4,5,5-tetramethyl-2-pyrazol-4-yl-1,3,2-dioxaborolane (19 mg, 0.1 mmol), 2M aqueous sodium bicarbonate (60 μl, 0.12 mmol), 2 ml mixture of DME/water/ethanol (7:3:2), and dichloro-(triphenylphosphine) palladium(II) (3 mg, 0.04 mmol). The reaction vial was capped, subjected to Personal Chemistry microwave irradiation at 140° C. for 20 minutes. After cooling, this reaction mixture was taken up with ethyl acetate (10 ml), filtered through a layer of celite, washed with ethyl acetate (2×10 ml), and decanted into a separatory funnel. The organic phase was washed sequentially with lithium hydroxide (0.1 N, 20 ml), saturated aqueous ammonium chloride (30 ml), brine, and dried over Na 2 SO4. The solution was concentrated in vacuo on a rotovap. The resulting mixture was then purified by chromatography via silica gel using 19:1 dichloromethane:methanol eluent to provide the desired compound, (6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5 -yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline, as pale yellow solid.
1 H NMR (400 MHz; CDCl 3 ) δ 7.83 (d, 1 H, J=2.0 Hz); 7.63 (d, 1 H, J=2.0 Hz); 7.45 (d, 1 H, J=2.0 Hz); 7.29 (dd, 1 H, J=8.2, 2.0 Hz); 7.13 (s, 1 H Hz); 7.04 (d, 1 H, J=2.0 Hz); 6.98 (d, 1 H, J=2.0 Hz); 6.46 (d, 1 H, J=8.2 Hz); 4.66 (d, 1 H, J=3.1 Hz); 4.42 (dd, 1 H, J=11.0, 2.7 Hz); 4.19 (s, 1 H); 3.94 (s, 3 H); 3.80 (m, 1 H); 2.10 (m, 1 H); 1.41-1.55 (s, 6 H). MS mz (M+H): 428.9.
B. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 14A above, but replacing (6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline with other compounds of formula I, or replacing 4,4,5,5-tetramethyl-2-pyrazol-4-yl-1,3,2-dioxaborolane with other dioxaborolane derivatives, the following compounds of formula I were prepared.
(6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline; (6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1 H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate; (6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-dimethylisoxazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate; and (6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-dimethylisoxazol-4-yl)-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline. diethyl (6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate; diethyl ((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate; and (6aR, 12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carbonitrile.
C. Preparation of a Compound of Formula I, varying R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , and X
Similarly, following the procedure of 14A above, but replacing (6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline with other compounds of formula I, or replacing 4,4,5,5-tetramethyl-2-pyrazol-4-yl-1,3,2-dioxaborolane with other dioxaborolane derivatives, other compounds of Formula I are prepared.
EXAMPLE 15
Several compounds of Formula I prepared as shown in the above procedures were characterized by NMR and mass spectrometry. For example:
2-((6aS,12aR-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol
1 H NMR (400 MHz, CDCl 3 ) δ 1.36(s, 3H), 1.46(s, 3H), 2.01(apparent dt, J=12.1, 3.5 Hz, 1H), 3.4(bs, 1H), 3.74(dd, J=12.1, 10.9 Hz, 1H), 4.1(bs, 1H), 4.25(ddd, J=189, 3.9, 1.6 Hz, 1H), 4.56(d, J=2.7 Hz, 1H), 7.28(d, J=10.1 Hz, 1H), 7.32(dd, J=8.6, 2.3 Hz, 1H), 7.36(d, J=2.3 Hz, 1H), 7.45(d, J=1.5 Hz, 1H)
2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]guinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
1 H NMR (400 MHz, CDCl 3 ) δ 1.21(s, 3H), 1.48(s, 3H), 2.06(ddd, J=10.9, 10.9, 3.1 Hz, 1H), 3.92(t, J=10.9 Hz, 1H), 4.45(d, J=10.5 Hz, 1H), 4.46(bs, 1H), 4.5(dd, J=10.9, 3.2 Hz, 1H), 6.72(d, J=8.6 Hz, 1H), 6.78(d, J=8.6 Hz, 1H), 7.3(dd, J=8.6, 2.3 Hz, 1H), 7.34(d, J=8.6 Hz, 1H), 7.42(d, J=2.3 Hz, 1H), 7.6(s, 1H)
EXAMPLE 16
mRNA ASSAYS
Modulation of expression of ABCA1 mRNA levels by the compounds of the invention was determined in the following assays.
Induction of ABC1 in THP-1 cells, was measured using QuantiGene® branched DNA assay as per manufacturer's instructions. Cultures of THP-1 were grown to subconfluence in DMEM/10% FBS before replacement with DMEM/BSA and 10 and 3 μM concentrations of the test compounds in DMSO for 18-20 hours. After treatment of cells with compounds, the cells were lysed with lysis buffer at 37° C. for 20 minutes. The cell lysate and ABCA1 specific probe (Genospectra, Inc., Fremont, Calif.) mix were added to the 96 well capture plate and hybridized at 53° C. for 16-18 hours. The signal was amplified using the amplifier and label probes provided with the QuantiGene® assay followed by addition of a luminescent alkaline phosphatase substrate, dioxitane. Luminescence was quantified in Victor V plate reader.
Step 1
Cells are lysed to release mRNA in the presence of target probes. Target mRNA from lysed cells was then captured by hybridization and transferred to the Capture Plate.
Step 2
Signal amplification was performed by hybridization of the bDNA Amplifier and Label Probe.
Step 3
Addition of chemiluminescence substrate yielded a QuantiGene® signal proportional to the amount of mRNA present in the sample.
The compounds of the invention demonstrated increased ABCA1 gene expression in this assay relative to a DMSO control. Table 1 presents the relative fold increase in ABCA1 expression over DMSO for various compounds of the invention when tested at a concentration of 10 μM.
TABLE 1
ABCA1 Induction Fold Increase over DMSO Vehicle at 10 μM
FOLD
NUMBER
NAME
INCREASE
1.
2-(2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-
4.4
b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
2.
2-((6aS,12aR)-2-bromo-7,7-dimethyl(7,12,12a,6a-
5.1
tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-
hexafluoropropan-2-ol;
3.
2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a-
3.0
tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-
hexafluoropropan-2-ol;
4.
2-(2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
2.1
b]quinolin-9-yl)acetic acid;
5.
2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
3.5
b]quinoline-9-carboxamide;
6.
methyl 2-bromo-10-methoxy-7,7-dimethyl-7,12,12a,6a-
1.6
tetrahydrochromano[4,3-b]quinoline-9-carboxylate;
7.
1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a-
3.1
tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
8.
2-[7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-
3.0
tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-
hexafluoropropan-2-ol;
9.
2-[(12aS,6aS)-7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-
2.4
tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-
hexafluoropropan-2-ol;
10.
3-methylbut-2-enyl (6aS,12aR)-9-(dihydroxyboramethyl)-7,7-
1.5
dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-
carboxylate;
11.
3-methylbut-2-enyl 9-(dihydroxyboramethyl)-7,7-dimethyl-
1.7
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;
12.
3-methylbut-2-enyl 7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-
4.6
(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-
b]quinoline-3-carboxylate;
13.
3-methylbut-2-enyl 7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-
3.4
(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-
b]quinoline-2-carboxylate;
14.
7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-
3.1
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylic acid;
15.
3-methylbut-2-enyl 9-(dihydroxyboramethyl)-7,7-dimethyl-
1.8
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate;
16.
7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-
2.4
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylic acid;
17.
9-(dihydroxyboramethyl)-7,7-dimethyl-7,12-dihydro-6H-
1.8
chromeno[4,3-b]quinoline-3-carboxylic acid;
18.
1,1,1,3,3,3-hexafluoro-2-(4,7,7-trimethyl(7,12,12a,6a-
5.3
tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
19.
4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-
5.6
tetrahydrochromano[4,3-b]quinoline;
20.
4-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-
6.5
tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-
dione;
21.
4-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
5.6
b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;
22.
2-(4-ethoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-
4.8
b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
23.
4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
6.1
b]quinoline-9-carboxamide;
24.
1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7,7-dimethyl(7,12,12a,6a-
6.5
tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
25.
2-[7,7-dimethyl-4-(3-methylbut-2-enyloxy)(7,12,12a,6a-
4.0
tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-
hexafluoropropan-2-ol;
26.
2-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
5.0
b]quinolin-9-yl)acetic acid;
27.
3-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-
3.3
tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic acid;
28.
3-((12aR,6aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-
1.9
tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic acid;
29.
4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-
5.8
carboxamide;
30.
4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
5.3
b]quinoline-9-carboxamide;
31.
4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
5.5
32.
(12aS)-4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
4.9
b]quinoline;
33.
1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-
6.4
tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
34.
2-((6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-
4.5
tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-
hexafluoropropan-2-ol;
35.
methyl (2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-
4.3
(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-
b]quinolin-2-yl)}prop-2-enoate;
36.
(2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-
5.3
(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-
b]quinolin-2-yl)}-N,N-dimethylprop-2-enamide;
37.
(6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-
8.3
tetrahydrochromano[4,3-b]quinoline;
38.
(12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-
7.0
tetrahydrochromano[4,3-b]quinoline;
39.
3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-
3.4
(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-
b]quinolin-2-yl)}-N,N-dimethylpropanamide;
40.
methyl 3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-
2.1
(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-
b]quinolin-2-yl}propanoate;
41.
4-ethoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-
2.1
tetrahydrochromano[4,3-b]quinoline;
42.
1-(4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
3.8
b]quinolin-9-yl)ethan-1-one;
43.
1-(1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
4.1
b]quinolin-9-yl)ethan-1-one;
44.
1-methoxy-7,7-dimethyl-9-(trifluoromethy;1)-7,12,12a,6a-
2.2
tetrahydrochromano[4,3-b]quinoline;
45.
1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
4.9
b]quinoline-9-carboxamide;
46.
(6aS,12aR)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-
4.2
tetrahydrochromano[4,3-b]quinoline;
47.
(12aS,6aS)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-
3.6
tetrahydrochromano[4,3-b]quinoline;
48.
(6aS,12aR)-9-fluoro-4-methoxy-7,7-dimethyl-7,12,12a,6a-
3.7
tetrahydrochromano[4,3-b]quinoline;
49.
(12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-
1.7
tetrahydrochromano[4,3-b]quinoline-9-carboxylic acid;
50.
4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
5.0
b]quinoline-9-carboxamide;
51.
1,1,1,3,3,3-hexafluoro-2-(4-fluoro-7,7-dimethyl(7,12,12a,6a-
7.8
tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;
52.
((6aS,12aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-
9.5
tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;
53.
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
3.5
tetrahydrochromano[4,3-b]quinoline;
54.
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-
4.3
tetrahydrochromano[4,3-b]quinoline;
55.
(12aS,6aR)-9-fluoro-1-methoxy-7,7-dimethyl-7,12,12a,6a-
2.5
tetrahydrochromano[4,3-b]quinoline;
56.
(12aS,6aR)-9-ethoxy-1-methoxy-7,7-dimethyl-7,12,12a,6a-
4.8
tetrahydrochromano[4,3-b]quinoline;
57.
((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-
6.1
tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;
58.
amino(4-methoxy-7,7-dimethyl(7,12,12a,6a-
6.2
tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione;
59.
{[(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-
6.1
b]quinolin-9-yl))methyl]sulfonyl}methylamine;
60.
methylethyl 3-(4-methoxy-7,7-dimethyl-7,12,12a,6a-
4.4
tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
61.
methylethyl 3-(4-methoxy-7,7-dimethyl-7,12-dihydro-6H-
2.0
chromeno[4,3-b]quinolin-9-yl)benzoate;
62.
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-
10.6
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
63.
(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
3.5
tetrahydrochromano[4,3-b]quinoline-10-carbonitrile;
64.
2-((6aS,12aR)-1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-
2.5
tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-
hexafluoropropan-2-ol;
65.
2-((6aS,12aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-
3.2
tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-
hexafluoropropan-2-ol;
66.
2-((12aR,6aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-
2.5
tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-
hexafluoropropan-2-ol;
67.
2-(2,4-difluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-
3.3
b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
68.
2-(2,4-dichloro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-
2.7
b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
69.
2-(2-chloro-4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-
2.6
b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
70.
2-((6aS,12aR)-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-
4.0
b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;
71.
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-
9.5
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
72.
4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
8.4
tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-
dione;
73.
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3-thiadiazol-4-yl)-
8.0
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; and
74.
1-methoxy-7,7-dimethyl-9-(4-methyl(1,2,4-triazol-3-yl))-
7.9
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline.
75.
9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-
7.4
tetrahydrochromano[4,3-b]quinoline;
76.
4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-
6.0
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
77.
2-((12aS,6aR)-4-methoxy-7,7-dimethyl-2-phenyl(7,12,12a,6a-
5.3
tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-
hexafluoropropan-2-ol
78.
1-bromo-9-ethoxy-4-methoxy-7,7-dimethyl-7,12,12a,6a-
2.7
tetrahydrochromano[4,3-b]quinoline;
79.
1-bromo-4-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-
4.1
tetrahydrochromano[4,3-b]quinoline;
80.
1-(1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-
4.3
tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;
81.
1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-
1.9
tetrahydrochromano[4,3-b]quinoline-9-carboxamide;
82.
amino(1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-
2.0
tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione;
83.
1-bromo-4-methoxy-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-
2.7
tetrahydrochromano[4,3-b]quinoline;
84.
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-
8.6
ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
85.
(12aS,6aR)-9-bromo-1-methoxy-7,7-dimethyl-7,12,12a,6a-
8.0
tetrahydrochromano[4,3-b]quinoline;
86.
(12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-
8.4
tetrahydrochromano[4,3-b]quinoline;
87.
(12aS,6aS)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-
7.4
tetrahydrochromano[4,3-b]quinoline;
88.
9-(tert-butyl)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
6.8
tetrahydrochromano[4,3-b]quinoline;
89.
{[(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-
6.4
b]quinolin-9-yl))methyl]sulfonyl}methylamine;
90.
diethoxy[(1-methoxy-7,7-dimethyl(7,12,12a,6a-
7.6
tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]phosphino-1-one;
91.
[(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-
6.2
tetrahydrochromano[4,3-b]quinolin-9-
yl))methyl]diethoxyphosphino-1-one;
92.
4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
8.7
tetrahydrochromano[4,3-b]quinolin-9-yl)benzenecarbonitrile;
93.
(12aS,6aS)-1-methoxy-7,7-dimethyl-9-[4-(trifluoromethyl)phenyl]-
6.8
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
94.
(12aS,6aS)-1-methoxy-7,7-dimethyl-9-phenyl-7,12,12a,6a-
5.8
tetrahydrochromano[4,3-b]quinoline;
95.
(12aS,6aR)-9-ethynyl-1-methoxy-7,7-dimethyl-7,12,12a,6a-
4.3
tetrahydrochromano[4,3-b]quinoline;
96.
ethyl 4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
7.6
tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
97.
4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
5.7
tetrahydrochromano[4,3-b]quinolin-9-yl)benzenesulfonamide;
98.
[4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
5.2
tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]methan-1-ol;
99.
(12aS,6aR)-9-(4-fluorophenyl)-4-methoxy-7,7-dimethyl-
1.7
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
100.
1-(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-
3.0
tetrahydrochromano[4,3-b]quinolin-9-yl))-2-methoxybenzene;
101.
1-(4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-
4.0
b]quinolin-9-yl)ethan-1-one;
102.
4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-
4.2
tetrahydrochromano[4,3-b]quinoline;
103.
(12aS)-4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-
4.0
tetrahydrochromano[4,3-b]quinoline;
104.
4-fluoro-9-(2-methoxyphenyl)-7,7-dimethyl-7,12-dihydro-6H-
2.9
chromeno[4,3-b]quinolin-12-ol;
105.
(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-
3.6
tetrahydrochromano[4,3-b]quinolin-9-yl))[(4-
methylphenyl)sulfonyl]amine;
106.
4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
4.8
tetrahydrochromano[4,3-b]quinolin-9-yl)benzoic acid
107.
ethyl 4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
2.9
tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
108.
4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
4.7
tetrahydrochromano[4,3-b]quinolin-9-yl)benzamide;
109.
(12aS,6aR)-9-(4-fluorophenyl)-1-methoxy-7,7-dimethyl-
4.1
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
110.
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(2-methyl(1,3-thiazol-4-yl))-
6.0
7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;
111.
(12aS,6aR)-1-methoxy-7,7-dimethyl-9-pyrazol-3-yl-7,12,12a,6a-
4.7
tetrahydrochromano[4,3-b]quinoline;
112.
1-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-
1.7
tetrahydrochromano[4,3-b]quinolin-9-yl))-4-methoxybenzene;
113.
methyl 3-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
1.5
tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;
114.
3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-
2.7
tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]propanoic acid;
115.
(2E)-3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-
2.2
tetrahydrochromano[4,3-b]quinolin-9-yl))phenyl]prop-2-enoic acid;
116.
ethyl 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-
2.7
dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-
4-carboxylate;
117.
(6aR,12aS)-6a,7,12,12a-tetrahydro-N-(2-hydroxyethyl)-1-methoxy-
8.6
7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;
118.
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
4
chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic
acid;
119.
((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-
7.5
chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;
120.
((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-
4.2
chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;
121.
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
3.2
chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-
yl)methanone;
122.
(6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-9-
2.4
(methylsulfonyl)-6H-chromeno[4,3-b]quinoline;
123.
(6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-N,N,7,7-tetramethyl-
6.5
6H-chromeno[4,3-b]quinolin-9-carboxamide;
124.
2-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
3.3
chromeno[4,3-b]quinolin-9-ylsulfonyl)acetic acid;
125.
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
4.1
chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-
yl)methanone;
126.
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-
7.3
chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-
yl)methanone;
127.
((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
5.1
chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;
128.
((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-
2.7
chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-
yl)methanone;
129.
((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-
4.3
chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-
yl)methanone;
130.
((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-
4.2
chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;
131.
2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-
2
chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic acid;
132.
((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-
4.3
chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-
yl)methanone;
133.
((6aS,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-
3.8
chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-
yl)methanone;
134.
((6aR,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-
5.8
chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-
yl)methanone; and
135.
ethyl 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-
6.4
dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-1H-pyrazole-4-
carboxylate;
136.
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
4.1
chromeno[4,3-b]quinolin-9-yl)-1H-pyrazole-4-carboxylic acid;
137.
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
7
chromeno[4,3-b]quinolin-9-yl)-N,N-dimethyl-1H-pyrazole-4-
carboxamide;
138.
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
7.4
chromeno[4,3-b]quinolin-9-yl)1-1H-pyrazole-4-((1,1-dione-1,4-
thiazaperhydroin-yl)methanone);
139.
((6aS,12aS)-4-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-
2.8
chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-
yl)methanone.
140.
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
5.1
chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-
ethanesulfonylpiperazin-1-yl)methanone);
141.
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
7.1
chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-
dione-1,4-thiazaperhydroin-yl)methanone);
142.
2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-
5
chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-
ethanesulfonylpiperazin-1-yl)methanone);
143.
2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-
6.1
chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-
thiazaperhydroin-yl)methanone);
144.
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-
2.1
chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-
ethanesulfonylpiperazin-1-yl)methanone);
145.
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-
4.5
chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-
dione-1,4-thiazaperhydroin-yl)methanone);
146.
2-((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-
8.2
chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic acid;
147.
2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-
7
chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-
ethanesulfonylpiperazin-1-yl)methanone);
148.
2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-
11
chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-
thiazaperhydroin-yl)methanone);
149.
(6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-
5.5
dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;
150.
(6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-
12.5
dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;
151.
(6aR,12aS)-methyl 2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-
6.3
dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;
152.
(6aS,12aS)-methyl 2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-
6.1
dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;
153.
(6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-1-methoxy-7,7,12-
7.4
trimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;
154.
2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-
9.4
chromeno[4,3-b]quinolin-12(12aH)-yl)acetic acid;
155.
(6aR,12aS)-6a,7,12,12a-tetrahydro-12-isopropyl-1-methoxy-7,7-
2.7
dimethyl-6H-chromeno[4,3-b]quinoline;
156.
2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-
7.6
chromeno[4,3-b]quinolin-12(12aH)-yl)acetic acid;
157.
ethyl 2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-
3.3
chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;
158.
(6aR,12aS)-12-benzyl-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7-
9.2
dimethyl-6H-chromeno[4,3-b]quinoline;
159.
(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-
7.6
(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline;
160.
(6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-
4.7
(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline;
161.
(6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-
8.1
2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate;
162.
(6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-
7.7
2-(3,5-dimethylisoxazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-
carboxylate; and
163.
(6aS,12aS)-12-ethyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-
3.1
dimethyl-6H-chromeno[4,3-b]quinoline;
164.
(6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-
5.6
dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;
165.
(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-
7.4
dimethylisoxazol-4-yl)-9-(oxazol-5-yl)-6H-chromeno[4,3-
b]quinoline.
166.
(6aR,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-
12.5
dimethyl-6H-chromeno[4,3-b]quinoline; and
167.
(6aS,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-
7.9
dimethyl-6H-chromeno[4,3-b]quinoline.
168.
diethyl ((6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-
4
dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;
169.
(6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-
9.7
dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;
170.
methyl 3-((6aS,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-
2.3
chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;
171.
methyl 3-((6aR,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-
2.2
chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;
172.
(6aR,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-
1.7
dimethyl-6H-chromeno[4,3-b]quinoline;
173.
(6aS,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-
1.8
dimethyl-6H-chromeno[4,3-b]quinoline;
174.
(6aR,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-
1.9
dimethyl-6H-chromeno[4,3-b]quinoline;
175.
(6aS,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-
1.5
dimethyl-6H-chromeno[4,3-b]quinoline;
176.
(6aS,12aS)-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7,12-trimethyl-
2.9
6H-chromeno[4,3-b]quinoline;
177.
1-((6aS,12aS)-6a,7,12,12a-tetrahydro-2-iodo-4-methoxy-7,7-
2.6
dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-
4-carboxylic acid;
178.
1-((6aR,12aS)-6a,7,12,12a-tetrahydro-2-iodo-4-methoxy-7,7-
5.1
dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-
4-carboxylic acid.
179.
diethyl ((6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-
5.2
dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;
180.
diethyl (6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-
2.2
chromeno[4,3-b]quinolin-9-yl)methylphosphonate;
181.
diethyl ((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-
4.9
dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinolin-9-
yl)methylphosphonate;
182.
(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-
4.6
pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carbonitrile.
EXAMPLE 17
In Vivo Mouse Model
To confirm the in vitro activity of compounds that induce ABCA1 gene expression in vitro and to further profile for acceptable bioavailability, PK and lipogenic activity, compounds were initially screened in a single dose 5 h mouse model. Compounds were prepared as suspensions in 0.75% carboxymethylcellulose/0.1% Tween 80 and administered by gavage to male mice at a dose of 1-200 mpk along with a vehicle control group. Food was removed immediately prior to dosing and the mice were bled retro-orbitally at 1 h to measure approximate peak plasma drug levels and at necropsy (5 h), by cardiac puncture, to measure 5 h drug levels.
EDTA plasma was separated from the blood samples by centrifugation and used for measurement of plasma drug levels by LC-MS. Primary blood mononuclear cells (PBMC's) were freshly isolated from the packed blood cells by differential centrifugation. A liver sample was preserved in RNALater (Qiagen) and the whole intestine was rinsed in saline and snap-frozen in liquid N 2 . RNA was isolated from the liver, intestine and PBMC's from individual mice using a Tissuelyzer (Qiagen) and RNAeasy RNA purification kits (Qiagen) with DNAse treatment (Qiagen).
cDNA was prepared from each RNA sample and used to determine the expression levels of mouse mABCA1, mSREBP1c, mFASN (fatty acid synthase) and mCYc (cyclophilin A). All 4 genes were measured at the same time using a quadraplexed Taqman qPCR assay using custom gene-specific primer-probe sets. Data was normalized to mCYC and gene expression was expressed relative to the vehicle treated group (fold). Compounds that induced ABCA1 and achieved acceptable plasma concentrations at both 1 h and 5 h were analyzed in this model at additional concentrations to obtain dose response information.
The compounds of the invention induced expression of ABCA1 in this assay.
EXAMPLE 18
Cholesterol Efflux
The ability of the compounds of the invention to stimulate cholesterol efflux from cells is determined in the following assay.
RAW 264.7 cells are loaded with cholesterol as described in Smith et al., J. Biol. Chem., 271:30647-30655 (1996). Briefly, semi-confluent cells plated in 48-well dishes are incubated in 0.2 ml of DMEM supplemented with 4.5 g/L glucose, 0.1 g/L sodium pyruvate and 0.584 g/L of glutamine, 10% fetal bovine serum, 50 μg/ml acetylated low density lipoprotein (AcLDL) and 0.5 μCi/ml of [ 3 H]-cholesterol. After 18 hr, cells are washed two times with PBS containing 1% BSA and incubated overnight (16-18 hours) in DMEM/1% BSA to allow for equilibration of cholesterol pools. The cells are then rinsed four times with PBS/BSA and incubated for one hour at 37° C. with DMEM/BSA. Efflux medium (DMEM/BSA) containing either albumin alone (control), albumin plus HDL (40 μg protein/ml), or albumin plus apo A-I (20 μg/ml, Biodesign International, Kennebunk, Me.) is added and the cells are incubated for 4, 24, or 48 hours.
Cholesterol efflux is measured by removing the medium, washing the cell layer and extracting the cells. Cellular radioactivity is measured by scintillation counting after solubilization in 0.5 ml of 0.2M NaOH (Smith et al., J. Biol. Chem., 271:30647-30655 (1996)) or extraction in hexane:isopropanol (3:2 v/v) as described in Francis et al., J. Clin. Invest., 96, 78-87 (1995). The labelled phospholipid remaining in the medium is also determined by liquid scintillation counting. The efflux of cholesterol is expressed as the percentage of tritiated lipid counts in the medium over the total tritiated lipid counts recovered from the cells and medium (cpm medium/cpm (medium+lysate)×100).
Cholesterol efflux is also determined in THP-1 cells. Replicate cultures of THP-1 cells are plated in 48 well dishes using the method described (see Kritharides et al Thrombo Vasc Biol 18, 1589-1599, 1998). Cells are plated at an initial density of 500,000 cells/well. After addition of PMA (100 ng/ml), the cultures are incubated for 48 hr at 37 C. The medium is aspirated and replaced with RPMI-1640 medium containing 2 mg/ml of FAFA, 50 μg/ml of acetylated LDL and 3 μCi/ml of radiolabeled cholesterol. After an overnight incubation, the medium is aspirated, the wells washed extensively with PBS. 0.2 ml of RPMI-1640 medium containing 2 mg/ml of FAFA is added to each well. The compound of interest are added to a final concentration of 10 μM. After 4 hr, Apolipoprotein A1 (10 μg/ml) is added to some wells and the cultures incubated for 24 hr. The medium is harvested and assayed for radioactivity. The amount of radioactivity in the cell layer is ascertained by adding 0.2 ml of 2 M NaOH and counting the lysed cells. The percent cholesterol efflux is calculated as described above.
EXAMPLE 19
The relationship between ABCA1 expression and HDL levels are determined in the following in vivo assay.
Candidate compounds that increase ABCA1 expression in vitro and are pharmacologically active and available in vivo are administered daily at a predetermined dosage to 7-12 week old male C57B1/6 mice by gavage in 0.75% carboxymethylcellulose/0.1% Tween 80 or other pharmaceutically acceptable formulation and route of administration. Five hours after the final injection, fasted EDTA-plasma and appropriate tissues are collected for analysis. Plasma lipoproteins levels and HDL cholesterol are measured by FPLC using a Superose 6/30 column and online detection of the cholesterol in the eluate. In vivo changes in the expression of ABCA1, SREBP1c, FASN and other relevant genes are further confirmed by qPCR of the cDNA's prepared from tissue RNA.
The in vivo efficacy of candidate compounds to induce lipogenesis and increased triacylglycerol production and storage is evaluated by measuring hepatic SREBP1c gene expression by qPCR and plasma and tissue triacylglycerol concentrations.
A correlation between ABCA1 expression and HDL levels was observed in this assay.
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The present invention provides compounds useful for increasing cellular ATP binding cassette transporter ABCA1 production in mammals, and to methods of using such compounds in the treatment of coronary artery diseases, dyslipidiemias and metabolic syndrome. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser. No. 09/604,475, filed Jun. 27, 2000, the disclosure of which is herein incorporated by reference.
FIELD
[0002] This invention relates to an article comprising a stack of sheets that may be applied, for example, to protect substrates such as glass or plastic windows, signage or displays.
BACKGROUND
[0003] Windows and glass in public transportation vehicles such as buses or subway trains can be subjected to a tremendous amount of abuse. The windows can be damaged by both incidental scratching during cleaning or they can be maliciously damaged by vandalism. Vandals damage the windows by scratching or abrading the surface of the window with items such as lava rock, diamonds, abrasive papers or abrasive cloths. Vandals can also damage the window by painting or coloring the surface of the window. Cleaning processes have been defined to eliminate damage by painting or coloring. However, scratching of glass by vandals presents a significant problem. In one major city, for example, approximately 40 percent of the bus windows have been vandalized by scratching and close to 80 percent of the subway train windows. The public transportation officials now call this type of graffiti “scratchiti”. The best approach to stopping graffiti historically has been to remove the graffiti immediately once it appears. This graffiti prevention system which is known as “zero tolerance”, has been extremely successful in eliminating the written and painted vandalism. Scratched glass, however, is extremely difficult and expensive to repair and as a result, the zero tolerance approach to scratchiti prevention and elimination is cost prohibitive. The vandalism issue tarnishes the overall image of an entire city's transportation system. The vandalized glass leads to lower ridership because of the reduced perception of safety on the vehicle by the public. The vandalism ultimately leads to lost revenue for the public transportation system and substantially high repair costs.
[0004] Several approaches have been evaluated to combat the scrachiti problem. The first approach has been to repair the glass by a multi-step abrasion/polishing method to remove the scrachiti. The abrasion steps remove glass to the depth of the scratch with diamond abrasives and then with subsequently finer grades of diamond or aluminum oxide abrasives the surface of the glass is polished to its original appearance. The abrasive materials are expensive and the time required to completely abrade and polish the surface of the glass can be several hours depending on the depth of the damaged areas.
[0005] A second approach to eliminating the problem has been to apply a single permanent adhesive coated polyester sheet onto the surface of the window. The polyester sheet is thick enough to protect the window from scratching by diamonds, lava rocks and most abrasives. The sheet is typically applied onto the glass with a water solution to eliminate any trapped air. The application process takes about 5 to 10 minutes to complete. The sheet does a good job of protecting the window from most of the damage but the sheet is readily damaged and the damage is visible to the passengers. Removing the sheet is very time consuming taking about 15 to about 60 minutes depending on the amount of residue left on the window after removal of the sheet. Once the damaged sheet is removed, a new permanent adhesive coated polyester sheet needs to be applied. The time required to remove the adhesive coated polyester sheet, remove the adhesive residue from the glass, and apply a new permanent adhesive coated polyester sheet and reinstall the window can be close to 2 hours. Examples of single permanent adhesive coated polyester sheets which can be used to protect a window are 3 M™ Scotchshield™ Safety and Security Window Film and 3 M™ Sun Control Window Films , data sheet number 70-0703-7220-0 published in September 1996 by the 3M Company.
[0006] The replaced sheet can be quickly damaged once the vehicle is used again in public thus necessitating another costly and time consuming replacement.
[0007] The third approach commonly used to repair and protect windows from scratches is to coat the damaged window with an epoxy coating. ( Enhancement of Vehicle Glazing for Vandal Resistance and Durability , by Daniel R. Bowman, Mar. 25, 1996, available from the United States Transportation Research Board). The damaged window is typically first scrubbed clean before coating with an epoxy coating. The epoxy coating can be used to fill the defects on the windows and restore the window to a state of clarity where signs can be read through the window. To apply the coating, the window must be removed from the vehicle and the window must be cleaned and primed. The coatings are applied and cured in a clean environment. The coatings currently available however are easily scratched by the same method used to scratch the glass. Once the coating is damaged, it is difficult to apply a subsequent coating due to poor adhesion of the coating to the first layer. The process to replace the damaged coating with a new coating is time consuming and expensive.
[0008] Another approach to the problem is to apply a sacrificial window as a shield over an original non-damaged window. The vehicle's window is modified with a frame that has a channel designed for a sheet of polycarbonate or acrylic. The rigid self-supporting sheet is inserted into the channel and acts as a barrier to damage on the base window. The polycarbonate sheet can be easily scratched by intentional methods being used to scratch the glass. This approach requires extensive modification to the window frame. Furthermore, the material cost per repair can be excessive making this approach cost prohibitive.
[0009] U.S. Pat. No. 3,785,102 discloses a pad comprising a plurality of very thin polyethylene or polypropylene removable sheets, each sheet bearing a very thin coating of pressure sensitive adhesive on its top surface for removing dirt from shoes and an adhesive at the bottom surface so that each successive layer is removably adhered to successive bottom layers and eventually to the floor. There is no discussion regarding the clarity of such a pad.
[0010] 3M Masking and Packaging Systems Division sells a stack of sheets with adhesive that removes lint and pet hair under the trade names Pat It™ Lint and Pet Hair Remover , product data sheet numbers 70-0705-7091-9, 70-0705-0819-0 and 70-0705-7038-0 published by 3M Company in 1994.
[0011] Research Disclosure 24109 (May 1984) discloses transmissive strippable plastic sheets stacked on mirror surfaces or stacked reflective (mirror surfaced) strippable plastic sheets that can be removed successively as toner or dust build up on the mirrors used in the optical imaging systems of electrophotographic reproduction apparatus occurs. The adhesive joining the layers to one another are provided only about the border areas of the sheets which are outside the optical image path to minimize image quality losses.
[0012] JP 10167765A describes a method of cleaning windows by the application of an optically clear sheet of plastic film on the inner and outer surface of the glass. The film is comprised of polyvinyl chloride, polyacrylic acid, polyester or polycarbonate. The plastic film is thin and only a single sheet of plastic is described on each side of the glass. The sheet is removed when the sheet becomes soiled.
[0013] U.S. Pat. No. 5,592,698 discloses a tear away lens stack for maintaining visibility through a transparent protective eye and face shield of a racing vehicle drivers helmet which includes a tab portion having projections formed thereon to assist in grasping the tab portion for rapid tear away. No adhesive is used in the stack; rather the lenses are clipped together.
SUMMARY
[0014] The present invention provides an article comprising a stack of sheets wherein the sheets are designed to be removable from each other such that a fresh sheet can be exposed after a topmost sheet above is damaged and then removed. The stack of sheets includes a vertically staggered side edge that aids in the identification of the topmost sheet in the stack for removal thereof from the stack of sheets. The stack can be applied, for example, to the interior of bus or train windows to provide protection for the windows. As a sheet is damaged by graffiti artists, the topmost sheet of the article can be removed by trained maintenance personnel to reveal a clean undamaged sheet below.
[0015] The present invention provides an article comprising:
[0016] a stack of sheets, wherein each sheet independently comprises:
[0017] (a) a film, the film having a first side having a surface area, an opposite second side surface having a surface area;
[0018] (b) a bonding layer having a first side having a surface area and an opposite second side having a surface area, wherein the bonding layer is bonded via its first side to the second side of the film such that at least a center of the surface area of the second side of the film is in contact with the bonding layer, wherein at least about 50 percent of the surface area of the second side of the film has the bonding layer bonded thereto;
[0019] (c) an optional release layer coated on the first side of the film;
[0020] wherein each sheet is stacked upon another sheet such that except for a bottom sheet of the stack of sheets, the bonding layer of a sheet is in contact with the film or release layer, if present, of a sheet below;
[0021] wherein at least a portion of the side edges of the sheets are disposed in a vertically staggered arrangement with respect to one another thereby forming a vertically staggered side edge, and wherein the vertically staggered side edge includes indexing surfaces which allow for identification of a single sheet;
[0022] wherein a topmost sheet can be removed from the stack of sheets by pulling it away from the stack such that the sheet being removed from the stack as well as the sheets remaining with the stack do not delaminate;
[0023] wherein the stack of sheets when subjected to a visual acuity test using a 3 meter Snellen eye chart can allow an observer with 6 meter/6 meter vision to read a line on the eye chart which is indicative of about 6 meter/9 meter vision or better.
[0024] In a preferred embodiment of the article of the invention the article when subjected to a visual acuity test using a 3 meter Snellen eye chart can allow an observer with 6 meter/6 meter vision to read the line on the eye chart which is indicative of about 6 meter/6 meter vision or better.
[0025] In a preferred embodiment the first side of the film is not bonded to a bonding layer of the same sheet. In other words, preferably each sheet has a bonding layer coated on the second side of the film only.
[0026] In a preferred embodiment of the article of the invention the bonding layer is continuous.
[0027] In a preferred embodiment, the article of the invention when subjected to a 180° Peel Adhesion to Glass test leaves substantially no residue (more preferably no residue) on the glass.
[0028] In a preferred embodiment of the article of the invention the stack of sheets is transparent.
[0029] In a preferred embodiment of the article of the invention each sheet has a penetration resistance of at least about 0.5 kg, even more preferably at least about 1 kg, even more preferably at least about 2 kg, even more preferably at least about 2.5, even more preferably at least about 3 kg, even more preferably at least about 3.5 kg, and most preferably about 4 kg.
[0030] With respect to the article of the invention preferably the maximum haze value of the stack of sheets is less than about 10 percent, more preferably less than about 5 percent, and most preferably less than about 3 percent.
[0031] In a preferred embodiment of the article of the invention at least about 80 percent (more preferably at least about 90 percent, and most preferably about 100 percent) of the surface area of the second side of the film has the bonding layer bonded thereto.
[0032] Preferably the article of the invention comprises at least about 2 sheets, more preferably about 3 to about 10 sheets.
[0033] In a preferred embodiment of the article of the invention the release layer is present and the release layer of each sheet has a Taber abrasion resistance of about 25 percent or less, more preferably about 10 or less, and most preferably about 2 or less according to ASTM D1044-76 after 100 cycles.
[0034] In a preferred embodiment of the article of the invention the bonding layer comprises a material selected from the group consisting of acrylics, rubbers, polyolefins, and mixtures thereof.
[0035] In a preferred embodiment of the article of the invention the bonding layer comprises a pressure sensitive adhesive.
[0036] In a preferred embodiment of the article of the invention the bonding layer has a thickness ranging from about 5 to about 150 microns, more preferably about 10 to about 25 microns.
[0037] In a preferred embodiment of the article of the invention the film has a thickness ranging from about 25 to about 4000 microns, more preferably about 50 to about 1000 microns.
[0038] In a preferred embodiment of the article of the invention the film comprises a material selected from the group consisting of polyester, polycarbonate, acrylic, polyurethanes, poly acetyl, polyolefin based ionomers, ethylene vinyl acetate polymers, polyethylene, polypropylene, polyvinyl chloride, polystyrene, urethane acrylate polymers, epoxy polymers, epoxy acrylate polymers, and blends thereof.
[0039] In a preferred embodiment of the article of the invention the film further comprises of an additive selected from the group consisting of ultraviolet light absorbers, ultraviolet light stabilizers, flame retardants, smoke suppressants, antioxidants, and mixtures thereof.
[0040] In a preferred embodiment of the article of the invention the film comprises multiple layers.
[0041] In a preferred embodiment of the article of the invention each sheet has a tensile strength of about 20 to about 2000 kP, an elongation of about 5 to about 1000% and a tear strength of about 0.05 to about 5 kg. Even more preferably each sheet has a tensile strength of about 70 to about 1400 kP, an elongation of about 5 to about 500% and a tear strength of about 0.5 to about 2.5 kg. Most preferably each sheet has a tensile strength of about 350 to about 1000 kP, an elongation of about 20 to about 100% and a tear strength of about 1.5 to about 2.5 kg.
[0042] In a preferred embodiment of the article of the invention the release layer is present.
[0043] In a preferred embodiment of the article of the invention the release layer has a thickness ranging from about 0.1 to about 25 microns, more preferably about 2.5 to about 5 microns.
[0044] In a preferred embodiment of the article of the invention the release layer comprises a material selected from the group consisting of acrylates, methacrylates, urethanes, silicones, polyolefins, fluorocarbons and mixtures thereof.
[0045] In a preferred embodiment of the article of the invention the bonding layer of each sheet further comprises a component selected from the group consisting of flame retardents, smoke suppressants, antioxidants ultraviolet light absorbers, ultraviolet light stabilizers, and mixtures thereof.
[0046] In a preferred embodiment of the article of the invention the sheets are rectangular sheets of the same length and width.
[0047] In a preferred embodiment of the article of the invention the vertically staggered side edge is located at an edge of said article.
[0048] In a preferred embodiment of the article the vertically staggered side edge is located at a corner of said article.
[0049] In a preferred embodiment of the article the indexing surfaces have a shape selected from the group consisting of crescent shaped, rectangular, semicircular, and trapezoidal.
[0050] In a preferred embodiment of the article the vertically staggered side edge is positioned at a corner of said article and the indexing surfaces are crescent shaped having one concave edge and one convex edge.
[0051] In a preferred embodiment of the article the vertically staggered side edge has a width ranging from about 0.5 mm to 25 mm and has a length ranging from about 25 mm to about 50 cm although the length of the vertically staggered side edge may also extend along the entire length of an edge of the article.
[0052] In a preferred embodiment of the article the vertically staggered side edge is in a staircase configuration or a reverse staircase configuration.
[0053] The present invention also provides a construction comprising:
[0054] (i) an article comprising:
[0055] a stack of sheets, wherein each sheet independently comprises:
[0056] (a) a film, the film having a first side having a surface area and an opposite second side having a surface area;
[0057] (b) a bonding layer having a first side having a surface area and an opposite second side having a surface area, wherein the bonding layer is bonded via its first side to the second side of the film such that at least a center of the surface area of the second side of the film is in contact with the bonding layer, wherein at least about 50 percent of the surface area of the second side of the film has the bonding layer bonded thereto, wherein with respect to each sheet the first side of the film is not bonded to a bonding layer of the same sheet;
[0058] (c) an optional release layer coated on the first side of the film;
[0059] wherein each sheet is stacked upon another sheet such that except for a bottom sheet of the stack of sheets, the bonding layer of a sheet is in contact with the protective film or release layer, if present, of a sheet below;
[0060] wherein at least a portion of the side edges of the sheets are disposed in a vertically staggered arrangement with respect to one another thereby forming a vertically staggered side edge, and wherein the vertically staggered side edge includes indexing surfaces which allow for identification of a single sheet;
[0061] wherein a topmost sheet can be removed from the stack of sheets by pulling it away from the stack such that the sheet being removed from the stack as well as the sheets remaining with the stack do not delaminate;
[0062] wherein the stack of sheets when subjected to a visual acuity test using a 3 meter Snellen eye chart can allow an observer with 6 meter/6 meter vision to read a line on the eye chart which is indicative of about 6 meter/12 meter vision or better; and
[0063] (ii) a substrate to which the article is bonded via the bonding layer of the bottom sheet.
[0064] In a preferred embodiment of the article of the invention the substrate comprises a material selected from the group consisting of glass, metal, plastic, painted surfaces, wood, fabric, wallpaper, ceramic, concrete, mirrored surfaces, plastic/glass laminates, and combinations thereof.
[0065] In a preferred embodiment of the article of the invention the substrate is part of a structure. Most preferably the structure is selected from the group consisting of windows, walls, partitions, signs, bill boards, artwork, buildings, elevators, vehicles, furniture, doors. CRT displays, personal computer/organizer screens, touch screens, and membrane switches.
[0066] In a preferred embodiment of the construction
[0067] the structure comprises a vehicle comprising a window;
[0068] and the article is bonded via the bonding layer of the bottom sheet to the window.
[0069] Most preferably the vehicle is selected from the group consisting of buses, trains, and subways.
[0070] The present invention also provides a method comprising the steps of:
[0071] (a) applying an article as described above to a substrate via the bonding layer of the bottom sheet of the article;
[0072] (b) allowing the topmost sheet of the article to be damaged;
[0073] (c) removing the damaged topmost sheet of the article by identifying the topmost sheet in the stack with reference to the indexing surface and gripping the topmost sheet and pulling it away from the stack, in a manner such that neither the sheet being removed nor the stack of sheets which remains delaminates, in order to expose a lower sheet of the article which becomes the topmost sheet of the article.
[0074] In a preferred embodiment of the method, steps (b) and (c) are repeated at least once. More preferably steps (b) and (c) are repeated until the bottom sheet is removed, and the bottom sheet upon removal leaves substantially no adhesive residue (most preferably) on the substrate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0075] The accompanying drawings are included to provide a further understanding ot the present invention and are incorporated in and constitute a part of the specification. The drawings illustrate the embodiments of the present invention and together with the description serve to explain the principals of the invention. Other embodiments of the present invention and many of the advantages of the present invention will readily appreciated as the same become better understood by reference to the following description when considered in connection with the accompanying drawings, in which like reference numerals designate like parts throughout the figures.
[0076] [0076]FIG. 1 is a cross-sectional view taken along line 1 - 1 of the construction of FIG. 5.
[0077] [0077]FIG. 1 a is a cross-sectional view taken along line 1 a - 1 a of the construction of FIG. 5 a.
[0078] [0078]FIG. 1 b is a cross-sectional view taken along line 1 b - 1 b of the construction of FIG. 5 b.
[0079] [0079]FIG. 2 is a cross-sectional view taken along line 2 - 2 of the construction of FIG. 6.
[0080] [0080]FIG. 3 is a cross-sectional view taken along line 3 - 3 of the construction of FIG. 7 showing a person peeling away a damaged topmost sheet to reveal a new topmost sheet.
[0081] [0081]FIG. 4 is a cross-sectional view of the construction of FIG. 8 taken along line 4 - 4 showing a stack of four sheets which is undamaged. FIG. 4 is identical to FIG. 3 except that damaged topmost sheet has been removed.
[0082] [0082]FIG. 5 is a plan view of a construction comprising an article of the invention adhered to a window.
[0083] [0083]FIG. 5 a is a plan view of a construction comprising an article of the invention adhered to a window.
[0084] [0084]FIG. 5 b is a plan view of a construction comprising an article of the invention adhered to a window.
[0085] [0085]FIG. 6 illustrates a plan view of the construction of FIG. 5 wherein the topmost sheet of the article is being damaged by a rock.
[0086] [0086]FIG. 7 illustrates a plan view of the construction of FIG. 6 wherein the damaged topmost sheet is being peeled away to reveal an undamaged sheet.
[0087] [0087]FIG. 8 illustrates a plan view of the construction of FIG. 7 after the damaged sheet has been removed and an undamaged sheet has been revealed.
[0088] [0088]FIG. 9 illustrates a plan view of an article of the present invention having a staggered edge located at a corner of the article.
[0089] [0089]FIG. 9 a illustrates a plan view of an article of the present invention having a staggered edge located at an edge of the article.
[0090] [0090]FIG. 9 b illustrates a plan view of an article of the present invention having a staggered edge located at an edge of article.
DETAILED DESCRIPTION
[0091] Article
[0092] With respect to the article of the invention, preferably the stack of sheets has no effect on visual acuity. The test for the effect on visual acuity appears later herein. This test can be used to determine the effect of an observer to discern images when looking through the article of the invention.
[0093] Preferably the article (as well as the stack of sheets and each individual sheet) has a haze value of less than about 10 percent, more preferably less than about 5 percent, and most preferably less than about 3 percent.
[0094] The article of the invention as well as the sheets making up the article are typically colorless although they may optionally be tinted. The sheets may optionally have a graphic thereon which would typically be on the edge of each sheet.
[0095] Sheets
[0096] Preferably the article comprises at least about 2 sheets, typically about 3 to about 10 sheets. Preferably each sheet has the substantially the same length, width, and shape. In a preferred embodiment each sheet is rectangular in shape.
[0097] Each sheet preferably provides a protective barrier to preferably prevent damage to a substrate to be protected such as a glass window as well as any sheets below the exposed topmost sheet. The sheet preferably resists penetration and damage from conventional scratching tools such as razor blades, knives, lava rocks, abrasive cloths, diamonds and carbide tipped styli. Preferably at least one (more preferably each) sheet has a penetration resistance of at least about 0.5 kg, more preferably at least about 2 kg, and most preferably at least about 4 kg.
[0098] Effect on visual acuity and color preferably remain stable upon exposure to a variety of environmental conditions.
[0099] The sheet is preferably easily removable, preferably in a continuous piece. The following tests which evaluate the integrity and removability of a sheet can be used to help predict the removability of a sheet.
[0100] Preferably at least one sheet (more preferably each sheet as well as each film making up the sheet) has a tensile strength when subjected to ASTM D882 of about 20 to about 2000 kP, more preferably about 70 to about 1400 kP, and most preferably about 350 to about 1000 kP. Preferably at least one sheet (more preferably each sheet as well as each film making up each) has an elongation when subjected to ASTM D882 of about 5 to about 1000%, preferably about 5 to about 500 percent, and most preferably about 20 to about 100 percent.
[0101] Preferably at least one sheet (preferably each sheet as well as each film making up each sheet) has a tear strength when subjected to ASTM D1004 of about 0.05 to about 5 kg, more preferably about 0.5 to about 2.5 kg, and most preferably about 1.5 to about 2.5 kg.
[0102] Film
[0103] Preferably the film comprises a material selected from the group consisting of polyester, polycarbonate, acrylic, polyurethanes, poly acetyl, polyolefin based ionomers, ethylene vinyl acetate polymers, polyethylene, polypropylene, polyvinyl chloride, polystyrene, urethane acrylate polymers, epoxy polymers, epoxy acrylate polymers, and blends thereof. In one embodiment the film comprises multiple layers.
[0104] The thickness of the film depends on the type of damage that the film may be subjected to and the composition of the film. Typically the film has a thickness of about 25 to about 4000 microns for reasons of weight, visual acuity and economics, preferably about 50 to about 1000 microns and most preferably about 50 to about 250 microns.
[0105] The film can optionally further comprise stabilizers and fillers which enhance the durability of the film upon exposure to ultraviolet light and/or heat. Additives can also be incorporated into the film that reduce the flammability of the film or smoke generation during combustion.
[0106] Bonding Layer
[0107] The bonding layer preferably provides a stable bond between the film layers. It is intended to prevent premature separation of the sheets under the environmental conditions anticipated in the application. It preferably serves to act as an optically clear interface between the films. However, it must bond more readily to the film of the same sheet than to the film of the sheet below.
[0108] In a preferred embodiment the first side of the film is not bonded to a bonding layer. The bonding layer as well as the other layers making up a sheet preferably do not change color when subjected to environmental conditions. Furthermore, the stability of the bonding layer preferably should not change dramatically on exposure to a wide range of conditions.
[0109] The bonding layer may comprise a pressure sensitive adhesive system or a non-pressure sensitive adhesive system. Preferably the bonding layer comprises a pressure sensitive adhesive. The bonding layer preferably comprises a material selected from the group consisting of acrylics, for example, which are thermally cured, ultraviolet light cured, electron beam cured and can be solvent based, waterbased or 100 percent solids; rubbers, for example, which can be thermoplastic rubbers, block copolymers, natural rubbers or silicone rubbers; and polyolefins which can, for example, be ethylene vinyl acetate polymers, poly-alpha olefins (C 3 -C 10 ) copolymers or blends of poly-alpha olefins with ethylene or propylene based polymers; and mixtures thereof.
[0110] The bonding layer may optionally further comprise a component selected from the group consisting of tackifiers, oils, stabilizers, flame retardants, fillers, and mixtures thereof subject to obtain the desired properties. Preferably the bonding layer further comprises a component selected from the group consisting of ultraviolet light absorbers, ultraviolet light stabilizers and mixtures thereof. Preferably the component selected from the group consisting of ultraviolet light absorbers, ultraviolet light stabilizers and mixtures thereof is used in an amount to inhibit degradation of the article from ultraviolet radiation, preferably about 0.5 to about 1 percent by weight based on the total weight of the bonding layer.
[0111] Preferably at least about 80 percent, more preferably at least about 90 percent, and most preferably about 100 percent of the surface area of the second side of the film has the bonding layer bonded thereto. Preferably the bonding layer is continuous. Preferably any areas of the film not covered by the bonding layer are margin(s).
[0112] Preferably the bonding layer has a thickness ranging from about 5 to about 150 microns, more preferably about 10 to about 50 microns, and most preferably about 10 to about 25 microns.
[0113] Optional Release Layer
[0114] The optional release layer preferably prevents light scratching of the surface of the film and in addition can provide a release surface for the bonding layer on the sheet above. This optional release layer is preferably bonded to the film layer in a manner so as to maintain the bond after a variety of environmental exposures. In addition, the release layer preferably remains clear after environmental exposures. It preferably maintains scratch resistant over time. It preferably forms a stable adhesion to the bonding layer and provides a consistent surface for removal of the sheet above.
[0115] Preferably the release layer, if present has a thickness ranging from about 0.1 to about 25 microns, more preferably about 2.5 to about 5 microns.
[0116] Preferably the release layer comprises a material selected from the group consisting of acrylates, methacrylates, urethanes, polyolefins, silicones, fluorochemicals such as fluorocarbons, and mixtures thereof.
[0117] U.S. Pat. No. 5,633,049 describes a method of making a protective coating for thermoplastic transparencies particularly aircraft transparencies. The coating is prepared from a silica-free protective coating precursor composition comprising a multifunctional ethylenically unsaturated ester of acrylic acid, a multifunctional ethylenically unsaturated ester of methacrylic acid, or a combination thereof; and an acrylamide. Such a protective coating may be useful as a release coating for the article of the present invention.
[0118] The release layer may optionally further comprise a filler such as ceramer particles, for example, as described in U.S. Pat. No. 5,104,929, in order to provide enhanced abrasion resistance properties.
[0119] The adhesion of the bonding layer to the release layer can be adjusted, for example, by incorporation of flow additives such as silicones, acrylics or fluorochemicals to the release layer.
[0120] The release layer can optionally be selected to improve the Taber Abrasion Resistance of the sheet. Release materials which may provide good Taber Abrasion Resistance properties include but are not limited to multifunctional acrylates or methacrylates.
[0121] The release layer on the top surface of the film layer may provide uniform release performance across the sheet. Optionally, a differential release layer can be coated on the film surface. Such a differential release layer can be used to make the initial separation of a sheet from the stack of sheets easier. Differential release can be obtained, for example, by coating a material providing easy release at the edge and/or corner of the sheet and coating a material providing tighter release on the balance of the sheet surface.
[0122] Suitable multifunctional ethylenically unsaturated esters of (meth)acrylic acid are the polyacrylic acid or polymethacrylic acid esters of polyhydric alcohols including, for example, the diacrylic acid and dimethylacrylic acid ester of aliphatic diols such as ethyleneglycol, triethyleneglycol, 2,2-dimethyl-3,3-propanediol, 1,3-cyclopentanediol, 1-ethoxy-2,3-propanediol, 2-methyl-2,4-pentanediol, 1,4-cyclohexanediol, 1,6-hexamethylenediol, 1,2-cyclohexanediol, 1,6-cyclohexanedimethanol; the triacrylic acid and trimethacrylic acid esters of aliphatic triols such as glycerin, 1,2,3-propanetrimethanol, 1,2,4-butanetriol, 1,2,5-pentanetriol, 1,3,6-hexanetriol, and 1,5,10-decanetriol; the triacrylic acid and trimethacrylic acid esters of tris(hydroxyethyl)isocyanurate; the tetraacrylic and tetramethacrylic acid esters of aliphatic triols, such as 1,2,3,4-butanetetrol, 1,1,2,2,-tetramethylolethane, 1,1,3,3-tetramethylolpropane, and pentaerythritol tetraacrylate; the pentaacrylic acid and pentamethacrylic acid esters of aliphatic pentols such as adonitol; the hexaacrylic acid and hexamethacrylic acid esters of hexols.
[0123] Preferably the release layer is present and the release layer of at least one sheet (preferably each sheet) has a Taber abrasion resistance of about 25 or less (more preferably about 10 or less and most preferably about 2 or less) as measured according to ASTM D1044-76 after 100 cycles. The release layer is not required if the bonding layer is anchored well to the film. For example, the film surface coated with the bonding layer may be chemically primed or oxidized with a corona discharge treatment or flame treatment. The film surface not coated with the bonding layer would be free of surface treatments. This adhesion differential between the two sides of the film facilitates clean separation of sheets from the stack. The film may also be soluble in the solvents or monomers used for the bonding layer. By coating a bonding layer on a soluble film and curing or evaporating, the bonding layer can become entangled with the film. The adhesion of the bonding layer to the coated film surface is greater than adhesion to the laminated surface in the stack of sheets. due to the differential in adhesion, clean separation of a sheet from a stack can be obtained.
[0124] Optional Prime Layer
[0125] An optional prime layer can be used to provide an adhesion promoting interface between the bonding layer and the film of the same sheet. Alternatively the film surface can optionally be modified via corona discharge treatments in a variety of atmospheres or by using a flame in order to promote adhesion between the bonding layer and the film of the same sheet. A prime layer can be, for example, an aziridine based prime layer or a grafted surface such as an acrylamide/multifunctional acrylate polymerized into the film surface with high-energy radiation. Other examples of prime layers include, for example, acrylics, polyvinylidene chloride and solution coated polyesters.
[0126] A prime layer can be, for example, a high tack pressure sensitive adhesive with a composition similar to the bonding layer. It can also, for example, be a coextruded interface prepared as a component of the film or resin solution coated on the film.
[0127] Preparation of the Article of the Invention
[0128] The article of the invention can be made in a number of different ways. One method of making the article of the invention is to apply the optional release coating on the surface of a film. The release coating could be applied by roll coating, gravure coating, or by an air knife coating process, for example. Any solvent(s) present in the coating are evaporated in an oven. The release coating can then be cured with ultraviolet (UV) light or with an electron beam. Alternatively, the opposite surface of the film may optionally be primed either with a surface treatment such as corona treatment or a flame treatment. The prime could also be a chemical prime. The chemical prime could be pre-applied by the film supplier or applied, for example, by roll coating, gravure coating, or by an air knife coating process. The solvent(s) are evaporated from the priming layer. The prime layer may be coated with the bonding layer by a variety of methods including notch bar coating, curtain coating, or slot die coating of a solution or latex. Another method of applying the bonding layer is extrusion coating of a 100% solids bonding layer. Depending on the chemistry of the coating, the bonding layer material is dried and/or cured to form a finished polymer. When the bonding layer is tacky at room temperature the bonding layer is preferably protected by a smooth release film. A stack of sheets can be prepared by removing the release liner from the bonding layer and laminating the bonding layer to the release surface of an adjacent sheet. The end application dictates the number of sheets in the stack. The stack of sheets can be cut into a desired shape by die cutting with a steel rule die, laser or with a water jet.
[0129] Another approach to forming a stack of sheets is to prepare a film with a primed surface and an opposite release surface. An ultraviolet curable liquid bonding layer is applied to the primed surface of one film and laminated in the liquid state to the release surface of a subsequent film. The liquid is cured. An ultraviolet curable liquid bonding layer is applied to the primed surface of a third film and laminated to the exposed release surface of the first laminated sheets. The liquid is cured resulting in a stack of three sheets. This lamination and curing process can be repeated until the desired number of sheets in a stack is obtained.
[0130] Other approaches to making the article of the invention are also possible.
[0131] Application of Article to Substrate
[0132] The article of the invention can be applied to a substrate in a number of different ways. For example, it can be applied by spraying an alcohol/water solution such as a 25% isopropanol/75% water solution on to the surface of the substrate. The release liner is removed from the bottom sheet of the stack of sheets to expose a bonding layer and the exposed bonding layer is also sprayed with the same isopropanol/water solution. The substrate and the saturated bonding layer are brought into contact and the excess solution is removed from the interface with a roller or a squeegee. The stack of sheets could also be applied to a substrate with a dilute solution of dishwashing detergent in water such as for example a 0.5% Joy™ dishwashing detergent 99.5% water solution. The stack of sheets could also be applied directly to the substrate with high pressure lamination without a liquid interface. The stack of sheets could be applied to the substrate by applying an ultraviolet light curable coating on the substrate as the liquid interface. The stack of sheets is applied, the excess air is removed by a roller or squeegee and the coating is cured.
[0133] Vertically Staggered Side Edge
[0134] In the article of the invention at least a portion of the length of a side edge of the article has a vertically staggered side edge. As used herein “vertically staggered side edge” means that the side edges of adjacent individual sheets making up the stack of sheets (i.e., the article) are staggered (i.e., non-aligned) with respect to one another. The vertically staggered arrangement of the side edge of one sheet with respect to an adjacent sheet in the stack makes possible the easy identification of a single sheet (i.e., identification of a single sheet) for removal thereof from the stack of sheets.
[0135] In one preferred embodiment, the side edge of the article is in a “staircase” type arrangement wherein, with respect to each sheet in the stack, the next lower sheet in the stack extends beyond the side edge of the sheet above. In another preferred embodiment, the side edges of the sheets are staggered in a “reverse staircase” arrangement wherein, the respect to each sheet in the stack, the side edge of the next lower sheet in the stack is positioned inside of the side edge of the sheet above. In another preferred embodiment, the side edges of the sheets are staggered in an alternating arrangement wherein with respect to each sheet in the stack, the side edge of the next lower sheet is positioned inside or outside of the staggered side edge of the sheet above and, with respect to every second sheet in the stack, the side edges are in substantially vertical alignment with one another. Such an arrangement may be described as having a “sawtooth” side edge. Other arrangements are also within the scope of the invention. For example, a staggered side edge may have both a staircase and reverse staircase arrangement.
[0136] The staggered side edge of the article of the present invention may be positioned entirely along one side edge of the article or the staggered side edge may be positioned at a corner of the article. In a preferred embodiment, the staggered side edge is positioned at a corner of the article.
[0137] The article of the invention can be better understood by referring to the following FIGS. 1 to 9 b.
[0138] [0138]FIG. 1 is a cross-sectional view taken along line 1 - 1 of the construction of FIG. 5. The article 2 of the invention is bonded via bonding layer 44 to a glass window pane 4 . The article 2 comprises a stack of five sheets ( 6 , 8 , 10 , 12 , and 14 ) bonded together. Sheet 6 , which is the topmost sheet in FIG. 1, comprises top release layer 16 , inner film layer 18 , and lower bonding layer 20 . Sheet 8 comprises top release layer 22 , inner film layer 24 , and lower bonding layer 26 . Sheet 10 comprises top release layer 28 , inner film layer 30 , and lower bonding layer 32 . Sheet 12 comprises top release layer 34 , inner film layer 36 , and lower bonding layer 38 . Sheet 14 , which is the bottom sheet of article 2 , comprises top release layer 40 , inner film layer 42 , and lower bonding layer 44 .
[0139] [0139]FIG. 1 shows a preferred embodiment of the article of the present invention 2 having staggered edge 3 . In this embodiment of an article of the present invention, staggered edge 3 may be described as being in a “staircase” configuration. As shown in FIG. 1, along staggered edge 3 of article 2 , sheet 8 extends beyond side edge 7 of sheet 6 providing indexing surface 21 . Similarly, sheet 10 extends beyond side edge 9 of sheet 8 providing indexing surface 27 . Sheet 12 extends beyond side edge 11 of sheet 10 providing indexing surface 33 . Sheet 14 extends beyond side edge 13 of sheet 12 providing indexing surface 39 . Staggered side edge 3 including indexing surfaces 21 , 27 , 33 , and 39 provides a precise way to identify the individual sheets of the stack of sheets, thereby allowing a person to remove only a single sheet (for example, sheet 6 ) from the stack. As shown in FIG. 7, the staggered side edge 3 is positioned in a corner of article 2 . Often time, it will be desirable to position the corner having the staggered side edge away from easy reach of vandals, for example, in the upper corner of a window, in order to prevent the removal of the sheets. The remaining side edges of article 2 comprise individual sheets having side edges that are in vertical alignment with one another. In the embodiment of FIG. 1, indexing surfaces 21 , 27 , 33 , and 39 have a trapezoidal shape although other shapes for the indexing surface are also possible.
[0140] [0140]FIG. 2 is a cross-sectional view of the construction of FIG. 6. FIG. 2 shows the topmost sheet 6 being scratched 48 by rock 46 .
[0141] [0141]FIG. 3 is a cross-sectional view of the construction of FIG. 7 along line 3 - 3 showing a person peeling away the damaged topmost sheet 6 to reveal a new topmost sheet 8 . Since article 2 has staggered edge 3 , top sheet 6 can be accurately identified with reference to indexing surface 21 and may be quickly separated removed from the remaining sheets comprising the stack.
[0142] [0142]FIG. 4 is a cross-sectional view of the construction of FIG. 8 along line 4 - 4 showing a now four sheet stack of sheets which is undamaged, wherein the topmost sheet is now sheet 8 . FIG. 8 is identical to FIG. 7 except that damaged topmost sheet 6 has been removed.
[0143] [0143]FIG. 5 is a plan view of a construction comprising article 2 of the invention on a window. Staggered side edge 3 having indexing surfaces 21 , 27 , 33 , and 39 is shown in the upper right hand corner of the window 4 . An observer 53 can view a tree 50 through the undamaged window 4 and article 2 . A rim 52 extends around the window 4 .
[0144] [0144]FIG. 6 illustrates a plan view of the construction of FIG. 5 wherein the top sheet 6 of the article 2 is being damaged by a rock 46 .
[0145] [0145]FIG. 7 illustrates a plan view of the construction of FIG. 6 wherein the damaged sheet 6 is being peeled away to reveal an undamaged sheet 8 .
[0146] [0146]FIG. 8 illustrates how the observer 53 can now clearly view the tree 50 after the damaged sheet 6 of FIG. 7 has been removed and undamaged sheet 8 has been revealed.
[0147] [0147]FIGS. 1 a and 5 a present another embodiment of an article of the present invention having a staggered side edge 3 a in a “reverse staircase” configuration. In the reverse staircase configuration of FIG. 1 a , sheet 6 a extends beyond side edge 9 a of sheet 8 a providing indexing surface 21 a . Sheet 8 a extends beyond side edge 11 a of sheet 10 a providing indexing surface 27 a . Sheet 10 a extends beyond side edge 13 a of sheet 12 a providing indexing surface 33 a . Sheet 12 a extends beyond side edge 15 a of sheet 14 a providing indexing surface 39 a . Staggered side edge 3 a of article 2 a provides a precise way to identify the individual sheets comprising the stack of sheets thereby allowing a person to remove only a single sheet (for example, sheet 6 a ) from the stack. A plan view of the
[0148] [0148]FIG. 1 b and 5 b present another embodiment of an article of the present invention having an staggered side edge 3 b in an “alternating” configuration. Such an alternating configuration includes sheets having a staircase configuration and sheets having a reverse staircase arrangement relative to one another. For example, sheets 8 b and 10 b are in a staircase configuration and sheets 6 b and 8 b are in a reverse staircase arrangement.
[0149] In the article of the present invention the indexing surfaces may have any desired size and shape and may be located along one or more side edges of the article or may be positioned at a corner of the article. Typically and preferably the indexing surfaces are small in size in order to prevent vandals from visually detecting the presence of the stack of sheets and in order to prevent unwanted tampering with the article if detected. For article of the present invention having very small and tamper resistant indexing surfaces, it may be desirable to use a sharp instrument, for example, a dental pick or canine tooth scraper, at the indexing surface to assist in peeling back the topmost sheet of the stack of sheets. Preferably, the indexing surfaces have a width ranging from about 0.5 to about 25 mm, more preferably ranging from about 0.5 mm to about 1.5 mm and have a length ranging from about 1 cm to about 50 cm, more preferably ranging from about 1 cm to about 10 cm.
[0150] The shape of the indexing surface may also be selected to provide increased tamper resistance and other desirable features. For example, FIG. 9 shows a plan view of a preferred embodiment of the present invention having a staggered side edge in a staircase configuration and having preferred crescent shaped indexing surfaces. Referring to FIG. 9, article of the present invention 70 includes sheets 72 , 74 , 76 and 78 . Each sheet comprises a film layer, a bonding layer, and optionally a release layer (the layers comprising the sheets are not shown individually in FIG. 10). Article 70 is rectangular in shape having linear side edges portions 80 , 82 , 84 , and 86 and radiused corners 88 , 90 , 92 , and 94 . In this embodiment, linear side edges 80 , 82 , 84 , and 86 comprise the side edges of individual sheets 72 , 74 , 76 , and 78 which are in vertical alignment with one another. Radiused corner 94 has a vertically staggered side edge defining indexing surfaces 96 , 98 , and 100 which may be described as being crescent in shape. Crescent shaped indexing surfaces 96 , 98 , and 100 are formed by varying the radius of curvature of the sheets 72 , 74 , 76 , and 78 at radiused corner 94 . As shown in FIG. 9, the crescent shaped indexing surfaces have a maximum width at the center and narrow at each end where the side edges of the sheets come into vertical alignment at sides 80 and 86 .
[0151] Various other embodiments of a staggered side edge may be envisioned and the present invention is not intended to be limited by the location, indexing surface shape and size, configuration, or number of individual staggered edges on an article of the present invention. Representative examples are shown in FIGS. 9 a - 9 b . For example, FIG. 9 a presents a plan view of an article of the present invention having a staggered side edge in a staircase configuration located along a portion of one edge of the article. FIG. 9 b presents a plan view of an article of the present invention having a staggered side edge in a staircase configuration along an entire edge of the article.
[0152] Crescent shaped indexing surfaces such as those shown in FIG. 9 may be preferred for several reasons. First, crescent shaped indexing surfaces tend to be particularly resistant to tampering by vandals. Since the staggered edge comprises a series of smooth curves of increasing radii of curvature that substantially converge at the vertically aligned side edges, the staggered side edge has no angled corners. Angled corners are particularly susceptible points of attack for vandals desiring to remove one or more layers from the stack of sheets. Further, when manufacturing articles of the present invention, it is typically necessary to remove the trim pieces that are generated when a staggered edge is cut into a stack of sheets. Since the trim pieces generated for crescent-shaped indexing surfaces substantially converge to a point at both ends, a manufacturing worker may easily grasp and strip all of the trim pieces in one motion. This feature is particularly attractive from a manufacturing standpoint since the trim or excess may be removed quickly with manual labor.
[0153] Articles of the present invention having staggered edges may be prepared by a variety of methods. For example, the various sheets making up the article are first cut to the desired size and shape and are then stacked upon one another to form an article of the present invention having a staggered edge. In a preferred method, the stack of sheets is first prepared and cuts are then made in the stack of sheets at the desired location and at the proper depth to provide a staggered edge. Following the cutting operation, the trim pieces are preferably removed to provide the staggered edge. Suitable methods for cutting the stack of sheets to form a staggered edge include, for example, die cutting with a steel rule die, laser cutting, or water jet cutting. A preferred cutting method utilizes an 80-500 W, slow flow CO 2 laser such as that commercially available under the trade designation “EAGLE LASER” from Laser Machining Inc., Somerset, Wis. The intensity of the laser may be adjusted to provide the desired depth of cut into the stack of sheets for forming the staggered side edge. When laser cutting, it may be desirable to cover the surface of the stack of sheets with a removable premask to prevent the unwanted deposition of smoke and deris from the cutting process on the surface of the stack of sheets.
[0154] Test Methods
[0155] Penetration Resistance
[0156] A white painted steel panel from Advanced Coating Technologies in Hillsdale Mich. is used as a base. A 50 mm×150 mm test sample is secured to the painted surface of the steel panel using a 100 mm×50 mm piece of No. 232 Scotch™ Masking Tape from 3M Company along the long edges of the sample such that a 125 mm×50 mm portion of the sample is in direct contact with the painted panel. (In the case of a sheet or stack of sheets the exposed adhesive layer is placed in contact with the painted panel.) The panel with the sample on the top surface is placed onto an electronic balance with a capacity of 20 kg. The balance is tared to the combined weight of the panel and sample. Using a stainless steel coated industrial single edge razor blade, apply a force of 0.5 kg to the test sample and hold for 2 seconds. Remove the blade from the test sample and repeat identically the force application and removal at a site 0.5 cm away from the original test site. Repeat the force application and removal at a site 0.5 cm away from the second site and at least 0.5 cm away from the first site to thus obtain 3 replicates at this force level. Color each force application test area with a black Sharpie™ felt tipped permanent marker from the Sanford Corp. The ink will flow through a penetrated area of the test sample and produce a mark on the white metal panel. Remove the test sample from the base panel and observe any marks on the base panel. If no marks are present the sample has passed the test. If any marks are present the sample has failed the test. Repeat the test using the following forces in the test: 1 kg, 1.5 kg, 2 kg, 2.5 kg, 3 kg, 3.5 kg, and 4 kg. The force required to penetrate the sample is recorded.
[0157] Effect of Sample on Visual Acuity of Observer
[0158] An observer with 6 meter/6 meter vision is positioned 3 meters from a 3 Meter Snellen eye chart, covers one eye and read with the uncovered eye the line which corresponds to 6 meter/6 meter vision. The observer will be considered to have 6 meter/6 meter vision if the observer has that vision unaided or has that vision with corrective lenses as long as the corrective lenses are worn during the testing. A 75 mm×75 mm sample of the article or material to be evaluated is then placed 3 centimeters in front of the observer's uncovered eye while the other eye remains covered to determine if the sample causes a loss of visual acuity. If the sample has a protective release liner, the release liner is removed prior to conducting the test. If the viewer can still read the line of letters indicative of 6 meter/6 meter vision it is considered that there is no interference with visual acuity caused by the sample. If the line indicative of 6 meter/6 meter vision cannot still be read the smallest line which can still be read is recorded, (For example 6 meter/9 meter, 6 meter/12 meter, 6 meter/15 meter, 6 meter/18 meter, etc.).
[0159] Appearance After 120 Hours at 23° C. and 180 Degree Peel Adhesion Between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film
[0160] A supported film is prepared as follows. A 105 mm×305 mm piece of 467 VHB™ Transfer Adhesive from 3M Company is removed from a roll. The transfer adhesive is an acrylic adhesive coated on a paper liner where both surfaces of the paper liner were treated with a differential silicone release such that the adhesive releases from one side of the liner easier than the other side. The sheet of transfer adhesive was laminated with a rubber roller to the entire surface of a 100 mm×300 mm rectangular painted white metal panel from Advanced Coatings Technology of Hillsdale, Mich. The release liner is removed from the transfer tape exposing the adhesive on the entire surface of the metal panel. To the adhesive is applied a 110 mm×320 mm film in such a way that film/adhesive/panel laminate is free of bubbles. The film is applied to the panel such that the release surface (the release layer or the surface of the first side of the film if there is no release layer present) is on the opposite surface of the film from the adhesive coated panel. Any excess film and adhesive was trimmed away.
[0161] To this panel supported film is laminated a 25 mm×150 mm sample of the sheet to be tested. (The sheet to be tested typically comprises a film with a bonding layer coated on one surface thereof.) The sample sheet is bonded to the panel supported film via its bonding layer. A rubber roller is used and in such a way that 100 mm of the sheet is bonded onto the panel supported film and 50 mm of the sheet hangs freely over the edge of the panel supported film. This assembly is allowed to dwell for 120 hours at room temperature and about 50% relative humidity (R.H.).
[0162] The over-hanging edge of the sample sheet is clamped to a sensor of a Slip-Peel Tester Model SP-102C-3090 adhesion tester (IMASS Inc. Accord, Mass.). The rest of the assembly is firmly clamped onto a carriage of the Slip-Peel Tester. As the carriage moves upon operation of the tester the sheet sample is peeled from the panel supported film at a rate of 228.6 cm/min and at an angle of 180 degrees. The average force required to remove the sheet sample from the panel-supported film over a 2-second test period is recorded. The test was conducted at about 23° C. and about 50% relative humidity.
[0163] Typical 180 degree peel adhesion values for a sheet of the article of the invention range from about 50 to about 2000 g/2.54 cm. The 180 degree peel adhesion values at the lower end of the range facilitate easy stripping of one sheet from another sheet. The 180 degree peel adhesion values at the upper end of the range make stripping of the sheets more challenging but the integrity of the stack (the ability of the stack to resist premature separation) can be maintained better when vandals scratch the surface of the stack. The preferred 180 degree peel adhesion range is about 500 to about 1500 g/2.54 cm. The most preferred 180 degree peel adhesion range is about 750 to about 1250 g/2.54 cm.
[0164] Appearance After Heat Aging and 180 Degree Peel Adhesion Between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film
[0165] The 180 degree peel adhesion force between a bonding layer on a sheet sample and the surface of an adjacent supported film is evaluated as described in the test method entitled “180 Degree Peel Adhesion Between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film” except the assembly is aged for 5 days at 80° C. The assembly is examined for discoloration, blistering, and adhesive residue. Preferably the test sample is not discolored or blistered. The test sample is allowed to equilibrate to room temperature for 2 hours prior to testing. The test was conducted at about 23° C. and 50% relative humidity.
[0166] The 180 degree peel adhesion value of a sheet of the article of the invention should preferably be stable compared to the room temperature adhesion value measured according to the test entitled “Appearance After 120 hours at 23° C. and 180 Degree Peel Adhesion Between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film”. The 180 degree peel adhesion after heat aging preferably should not increase more than about 50% and should not decrease more than about 25%. The test sample preferably leaves no residue such as adhesive residue upon removal.
[0167] Appearance After Continuous Exposure to Condensing Humidity and 180 Degree Peel Adhesion Between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film
[0168] The adhesion force between a bonding layer of a sheet and the surface of an adjacent supported film is evaluated as described in the test method entitled “Appearance After 120 hours at 23° C. and 180 Degree Peel Adhesion Between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film” except that the assembly is first continuously aged in a chamber that is maintained at 38° C. and 100% relative humidity for days prior to appearance evaluation and 180 degree peel adhesion testing. The assembly is examined for discoloration and blistering. The assembly is allowed to equilibrate to room temperature for 2 hours prior to testing for 180 degree peel adhesion. The test was conducted at about 23° C. and 50% relative humidity.
[0169] The 180 degree peel adhesion value of a sheet of the article of the invention should preferably be stable compared to the room temperature 180 degree peel adhesion value as measured according to the test method entitled “Appearance After 120 hours at 23° C. and 180 Degree Peel Adhesion Between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film”. The level of 180 degree peel adhesion after condensing humidity exposure preferably should not increase more than about 50% or decrease more than about 25%. The test sample preferably leaves no residue such as adhesive residue upon removal.
[0170] Appearance After an Environmental Cycling Test and 180 Degree Peel Adhesion Between a Bonding Layer on a Sheet Sample and the Surface of a Supported Adjacent Film
[0171] The adhesion force between a bonding layer on a sheet sample and the surface of a supported adjacent film is evaluated as described in the test method entitled “Appearance After 120 hours at 23° C. and 180 Degree Peel Adhesion Between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film” except that prior to testing the assembly is first aged in a controlled environmental chamber that is programmed to conduct the following continuous cycle: 4 hours at 40° C./100% relative humidity (RH), followed by 4 hours at 80° C. and then followed by 16 hours at −40° C. The sample is exposed 10 times to this cycle. The sample is examined for discoloration and blistering. Preferably the aged sample does not experience discoloration or blistering. The sample is allowed to equilibrate to room temperature for 2 hours before 180 degree peel adhesion testing. The peel adhesion test was conducted at about 23° C. and about 50% humidity.
[0172] The 180 degree peel adhesion value of a sheet of the article of the invention should preferably be stable compared to the room temperature adhesion value as evaluated in the test method entitled “Appearance After 120 hours at 23° C. and 180 Degree Peel Adhesion Between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film”. The level of 180 degree peel adhesion of a sheet of the article of the invention after thermal cycling preferably should not increase more than about 50% or decrease more than about 25%. The test sample preferably leaves no residue such as adhesive residue on removal.
[0173] 180 Degree Peel Adhesion to Glass
[0174] A 100 mm×200 mm flat glass plate is cleaned with toluene and allowed to air dry prior to application of a sheet sample to be tested. (The sheet to be tested typically comprises a film and a bonding layer bonded to one side thereof.) The adhesion to glass is measured by bonding a 25 mm×150 mm of the sheet sample to be tested using a rubber roller such that no trapped air and 25 mm×50 mm of the sheet is hanging over the edge of the glass. The sheet is applied such that the bonding layer of the sheet is in contact with the glass. The sheet is allowed to dwell on the glass at least 10 minutes but less than 60 minutes. The glass plate is clamped onto the carriage of a Slip-Peel Tester Model SP-102C-3090 adhesion tester (IMASS Inc., Accord Mass.). The overhang of the sheet is clamped to a sensor of the tester. As the carriage moves upon operation of the tester the force to peel the sheet is measured at 228.6 cm/min at an angle of 180 degrees. The average force over a 2 second period is recorded. The test is conducted at about 23° C. and about 50% R.H.
[0175] Typically the 180 degree peel adhesion to glass of a sheet of an article of the invention is about 100 g/2.54 cm to about 5000 g/2.54 cm, preferably about 500 g/2.54 cm to about 3000 g/2.54 cm, and most preferably about 1500 g/2.54 cm to about 2500 g/2.54 cm. One hundred eighty degree peel adhesion above about 5000 g/2.54 cm is less preferred, because the sheet may be difficult to remove after a prolonged time on the glass. One hundred eighty degree peel adhesion below about 100 g/2.54 cm is less preferred, because the bond to the glass could potentially be disrupted when the individual sheets are removed from the stack.
[0176] The glass panel is inspected for residue left after the sheet sample is peeled from the glass. Preferably substantially no residue (such as adhesive residue) remains on the glass. Most preferably no visible residue (such as adhesive residue) remains on the glass. The percentage of the area of the test panel where the sample was initially applied on which any residue remained is recorded.
[0177] Haze Test
[0178] The haze of a sample is measured by using a Garner XL211 Hazeguard device. The procedure used is in accordance to ASTM D1003-95 with the following exceptions
[0179] 1. The sample size is rectangular with a minimum size of 40 mm×40 mm.
[0180] 2. The sample is scanned for areas of the maximum haze. These selected areas are measured and the maximum haze value is reported.
[0181] 3. The sample is allowed equilibrate at 23° C. and 50% R.H. for 72 hours prior to testing.
[0182] 4. If printed or embossed images or graphics are contained on the sample, those areas of the sample should be avoided when measuring the maximum haze of the sample.
[0183] 5. Prior to conducting the haze test, the release liner (if any) is removed from the sample.
[0184] Scratch Resistance
[0185] A 1.2 kg hammer manufactured by Collins Axe Company is provided. A tungsten carbide tipped stylus from General Tools Manufacturing Co. Inc. New York, N.Y. is taped securely to the very top of the metal head of the hammer such that the tip of the nail points in substantially the same downward direction as does the hitting end of the hammer head. The nail is positioned such that it is substantially perpendicular to the handle of the hammer. The stylus protrudes from the hammer 2.5 cm. The tape used is No 471 tape from 3M Company. The sheet sample is attached to a 100 mm×300 mm white painted metal panel and held securely in place. The hammer is held at the end of the handle while the carbide stylus bears the weight of the hammer. A straight edge is taped to the sheet sample as a guide. The hammer is pulled down the length of the panel at about 200 cm/min such that the weight of the hammer is on the stylus. The hammer is pushed back up the length of the panel. Each up and down motion consisted of one cycle. The number of cycles needed to scratch through the sample and into the white paint is reported.
[0186] The scratch resistance of a sheet or a film layer of an article of the invention typically ranges from about 5 to more than about 500 cycles, preferably greater than about 10 cycles, more preferably greater than 50 cycles and most preferably greater than about 100 cycles.
[0187] Taber Abrasion Resistance
[0188] A 7.5 cm diameter non-abraded circular sample of the material to be tested is cut such that a 1.25 cm hole is provided in the center of the sample. The haze of the non-abraded sample is then measured using a Gardner XL211 Hazeguard system. The Gardner XL211 Hazeguard system is balanced and calibrated to zero using the non-abraded sample. The sample is clamped in a fixture of a Taber abrader. The sample is abraded using the Taber Abrader with CS10 wheels and a 500 gram load for 100 cycles. The haze of the abraded sample is measured using the Gardner XL211 Hazeguard system. The difference in haze of the abraded surface and the non-abraded surface is recorded.
[0189] The Taber abrasion resistance value is the percentage difference between the haze value of the abraded sample and the non-abraded sample. Preferably the Taber abrasion resistance of the sample of the material being tested after 100 cycles is less than about 25 percent, more preferably less than about 10 percent, and most preferably less than about 2 percent.
EXAMPLES
[0190] The present invention will be better understood by referring to the following non-limiting examples. All parts, percentages, ratios, etc. in the examples are by weight unless indicated otherwise.
Example 1
[0191] A bonding material solution comprising 96 parts by weight of isooctyl acrylate and 4 parts by weight of acrylamide was prepared in a 50% heptane/50% ethyl acetate solution using 2,2′-azobis(isobutyronitrile) free radical initiator available under the trademark “VAZO” 64 from the E.I. DuPont Company, of Wilmington, Del.
[0192] The following components were added to a reaction vessel: 19.2 kg of isooctyl acrylate, 0.8 kg of acrylamide, 40 kg of heptane and 40 kg of ethyl acetate. While constantly stirring under a nitrogen atmosphere and controlling the temperature between 70-100° C., 270 grams of VAZO™ 64 was added to the vessel in three 90-gram increments. The resulting polymer had a conversion of 98%. The Brookfield viscosity was measured (#3 spindle at 12 rpm) at 2000-2800 cps at a solids level of 19-23%. The inherent viscosity of the polymer was 1.25-1.40 dl/gram.
[0193] A first sheet of film with a tacky bonding layer was prepared by coating the bonding material solution onto a second surface of a 15 cm×100 cm×125 micron thick optically clear biaxially oriented corona treated polyester film using a knife coater at a wet thickness of 175 microns. The second surface of the film was the corona treated surface of the film. The coated film was dried in an air convection oven for 10 minutes at 82° C. The dry thickness of the coating of the coated film was 20-25 microns. The tacky bonding layer of this first sheet was protected by laminating an optically clear silicone coated polyester film to the tacky bonding layer. The silicone coated polyester film was 1-2 PESTRD (P1)-7200 available from DCP Lohja Inc. of Lohja Calif. The surface opposite the bonding layer coated surface of the film will be referred to herein as the release surface.
[0194] A second sheet of film with a tacky bonding layer was prepared in a similar manner. The bonding layer of the second sheet was laminated to the release surface of the first sheet using a laminator with a steel roll and a rubber backup roll having a shore A hardness of 75 at a pressure of 32 N/cm 2 such that the bonding layer of the second sheet was in contact with the release surface of the first sheet. This sheet preparation and lamination process was repeated until a stack of four sheets was completed.
Example 2
[0195] Example 2 was identical to Example 1 except that the corona treated polyester film was 170 microns in thickness.
Example 3
[0196] Example 3 was identical to Example 1 except that the corona treated polyester film was 75 microns in thickness.
Example 4
[0197] Example 4 was identical to Example 1 except that the corona treated polyester film was 250 microns in thickness and the size of the corona treated polyester film was 15 cm×25 cm.
Example 5
[0198] Example 5 was identical to Example 1 except that a sufficient number of sheets were made and laminated together until a stack of 10 sheets was prepared.
Example 6
[0199] Example 6 was identical to Example 1 except that the film onto which the bonding material solution was coated was a 175 micron polyester film with a hard coating on the first surface which served as the release layer. This film and coating was obtained from the Furon Corporation of Worcester, Mass. under the product name 007 PET/0270x Hard coat. In addition, the side of the film opposite the release layer was corona treated prior to coating with the bonding material described in Example 1.
Example 7
[0200] A polished 22 cm×28 cm×250 micron thick film of clear transparent polycarbonate was obtained from General Electric under the tradename Lexan™ FR60. The film had a first surface and an opposite second surface. The film was coated on its first surface with a solution of 3M 906 hard coat, an acid-resistant acrylic based protective coating available from 3M Company, St Paul, Minn. in order to provide a release layer and an abrasion resistant surface on one side of the film. The coating solution was made by diluting to 16% solids 906 hard coat with a 50/50 mixture of isopropanol and n-butanol. To 100 grams of the diluted hardcoat solution, 0.075 gram of a leveling agent Dow 57, an alkoxy terminated polysilicone available from Dow Coming of Midland, Mich. was added. The coating was applied with a syringe to the first surface of the film in a vertical position approximately 10 microns wet. The sheet was dried 10 minutes at 82 degrees C. The coating on the film was cured with a 300 Watt high pressure mercury vapor lamps at a belt speed of approximately 30 meters per minute. The reflective parabolic lamp housing focused the light source on the coating. The curing unit was Model II 180133 AN from RPC Industries of Plainview, Ill. The resulting thickness of the hard coat was 1-2 microns.
[0201] A bonding material was prepared from 96 parts by weight of isooctyl acrylate and 4 parts by weight of acrylamide in a 50% heptane/50% ethyl acetate solution using VAZO™ 64 initiator as follows.
[0202] To a reaction vessel the following materials were added: 19.2 kg of isooctyl acrylate, 0.8 kg of acrylamide, 40 kg of heptane and 40 kg of ethyl acetate. While constantly stirring under a nitrogen atmosphere and controlling the temperature between 70-100° C., 270 grams of VAZO™ 64 was added to vessel in three 90 gram increments. The resulting polymer solution had a conversion of 98%. The Brookfield viscosity was measured (#3 spindle at 12 rpm) at 2000-2800 cps at a solids level of 20%. The inherent viscosity of the polymer solution was 1.40 dl/gram.
[0203] The polymer solution was coated on 15 cm×30 cm×50 micron thick optically clear biaxially oriented silicone coated optically clear polyester film (transfer film) using a knife coater at a wet thickness of 175 microns. The silicone coated polyester was 1-2 PESTRD (P1)-7200 from DCP Lohja Inc. of Lohja Calif. The coated film was dried in an air convection oven for 10 minutes at 82° C. in order to form a transfer tape. The dry thickness of the coated layer was 20-25 microns. The coating was considered to be a bonding layer. The transfer tape was laminated to the non-hard coated surface of the Lexan™ FR60 sheet via the bonding layer of the transfer tape. Any excess Lexan™ FR60 sheet and transfer tape were trimmed so that the trimmed laminate had areas with complete coating of the bonding layer. Four of these trimmed laminates were prepared.
[0204] A stack of sheets was produced by removing the optically clear polyester release film from the bonding layer of the first trimmed laminate and laminating it to the release coated surface of the second trimmed laminate using a laminator with a steel roll and a rubber backup roll with a shore A hardness of 75 at a pressure of 32 N/cm 2 . The optically clear polyester release film was removed from the third trimmed laminate and the third trimmed laminate was laminated to the release coated surface of the first two trimmed laminates. This was repeated until a stack of four trimmed laminates was produced.
Example 8
[0205] Example 6 was repeated except the bonding layer was comprised of polyhexene. The film onto which the bonding material layer was coated was a 175 micron thick optically clear polyester with a 0270x hard coat as described in Example 6 from the Furon Corporation of Worcester, Mass.
[0206] A bonding material was prepared using a polyhexene with an inherent viscosity of 3.0 dl/gram. The polyhexene was prepared using a process described in U.S. Pat. No. 5,644,007 issued on Jul. 1, 1997 and assigned to 3M Company. The polyhexene was prepared using 0.2-0.3 g of a Ziegler-Natta catalyst Lynx™ 715 per kg of monomer. Lynx™ 715 is TiCl 4 supported on MgCl 2 powder which is commercially available from Catalyst Resources Inc. This catalyst is discussed in Boor, Ziegler - Natta Catalysts and Polymerizations, “Polymerization of Monomers ,” Ch. 19, pp. 512-562, Academic. The conversion rate was 15%. The bonding material was coated on the surface of the film opposite the release layer of the film.
Comparative Example 9
[0207] Four layers of Scotch™ 375 packaging tape from 3M Company in St. Paul, Minn. were laminated together using a laminator with a steel roll and a rubber backup roll with a shore A hardness of 75 at a pressure of 32 N/cm 2 . Each layer of tape was 10 cm×15 cm and comprised a 50 micron biaxially oriented polypropylene backing and a 37 micron rubber based adhesive coated on one surface thereof. The adhesive on the bottom sheet of the stack was protected by a silicone coated optically clear polyester release liner. The polyester release liner was 1-2 PESTRD(P1)-7200 from DCP Lohja Inc. of Lohja Calif. The liner was removed from each tape and the tapes were laminated together such that the adhesive layer of one tape was in contact with the film layer of the tape below except for the bottom piece of tape.
[0208] Example 1-8 and Comparative Example 9 were subjected to various tests. The tests and the results obtained are reported in the table below.
[0209] Example 1-8 and Comparative Example 9 were subjected to various tests. The tests and the results obtained are reported in the table below.
Table Comparative Example Example Example Example Example Example Example Example Example 1 2 3 4 5 6 7 8 9 1. Effect of Sample of 6/6 6/6 6/6 6/6 6/6 6/6 6/6 6/6 6/12 Visual Acuity (meter/meter) 2. Penetration Resistance 1.0 1.0 0.5 1.5 1.0 1.0 1.5 1.5 0.5 (kg) 3. Taber Abrasion 18 18 18 18 18 2 2 0.3 17 Resistance (% haze difference between abraded and non abraded samples after 100 cycles of abrasion on a Tabor Abrader) 4. Scratch Resistance 59 110 10 208 59 115 125 115 3 (Cycles) 5. Haze % 3.8 2.8 2.3 4.1 3.3 2.9 3.0 2.9 7.5 6a. Appearance After 120 735 585 940 Not 735 207 889 73 207 hours at 23° C. and 180 tested Degree Peel Adhesion between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film. (grams / 2.54 cm) 6b. Appearance of sample No No No Not No No No change No No after 120 hours at 23° C. change change change tested change change change change and observations of the surface where sheet was removed. (No change = no residue on removal, no blisters in the sample and no discoloration) 7a. Appearance after Heat 833 695 980 Not 833 683 889 132 683 Aging (120 hours at 23° tested C.) and 180 Degree Peel Adhesion Between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film. (g / 2.54 cm) 7b. Appearance of sample No No No Not No 5% residue 15% residue No 5% residue after 120 hours at 80° C. change change change tested change small large change small and observation of surface blisters blisters blisters where sheet was removed. no dis- no dis- no dis- (No change = no coloring coloring coloring residue on removal, no blisters in the sample and no discoloration) 8a. Appearance After 865 685 1025 Not 865 268 927 69 268 Continuous Exposure to tested Condensing Humidity (120 hours at 33° C. and 100% R.H.) and 180 Degree Peel Adhesion between a Bonding Layer of a Sheet and the Surface of an Adjacent Supported Film. (g / 2.54 cm) 8b. Appearance of sample No No No Not No No Small No No after 120 hours at 38° C. / change change change tested change change blisters change change 100% RH and observation of surface where sheet was removed. (No change = residue on removal, no blisters in the sample and no discoloration). 9a. Appearance After an 815 655 1120 Not 815 357 575 73 357 Environmental Cycling Test tested and 180 Degree Peel Adhesion between a Bonding Layer on a Sheet Sample and the Surface of a Supported Adjacent Film. Adhesion between sheets after 5 thermal cycles (g / 2.54 cm) One thermal cycle consists of 4 hours at 80° C., 4 hours at 38° C. and 100% R.H. and 16 hours at −40° C. 9b. Appearance of sample No No No Not No 5% residue 15% residue No 5% residue after 5 thermal cycles and change change change tested change small blisters large change small observation of surface no dis- blisters blisters where sheet was removed. coloring no dis- no dis- (No change = no coloring coloring residue on removal, no blisters in the sample and no discoloration).
[0210] The foregoing detailed description and Examples have been given for clarity of understanding only. No unnecessary limitations are to be understood therefrom. The complete disclosures of all patents, patent applications, and publications are herein incorporated by reference as if individually incorporated. Various modifications and alterations of this invention will become apparent to those skilled in the art from the foregoing description without departing from the scope and the spirit of this invention, and it should be understood that this invention is not to be unduly limited to the illustrative embodiments set forth herein.
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This invention relates to an article comprising a transparent stack of sheets that may be applied, for example, to protect substrates such as glass or plastic windows, signage or displays. The stack of sheets has a vertically staggered side edge which allows for easy identification of the topmost sheet in the stack for removal therefrom from the stack of sheets. The topmost sheet can be peeled away after it is damaged to reveal an undamaged sheet below. The invention also relates to the protected substrates and a method of protecting substrates such as glass or plastic windows, signage and displays from vandalism or other surface damage by adhering the stack of sheets to the substrate to be protected and subsequently pulling a topmost sheet away from the stack after it becomes damaged.
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[0001] This application claims priority to U.S. Provisional Patent Application No. 60/857,964 filed on Nov. 9, 2006 entitled METHOD AND DEVICE FOR FIXATION OF OPHTHALMIC TISSUE.
BACKGROUND
[0002] Ocular maladies present numerous challenges to health care providers. Cataracts provide one such malady. To treat cataracts, physicians often replace the problematic natural lens of the eye with an artificial intraocular lens (IOL). IOLs may have side members, referred to as haptics, which help stabilize the lens within the eye. In some cases, a clip is connected to the haptic or lens optic by the lens manufacturer. After inserting the IOL into the eye, the physician then attempts to secure the IOL in the eye by connecting the clip to ocular tissue such as the inner iris. Doing so, however, often leads to iris chafing brought on by the interaction between the clip and the inner iris, an area of the eye that is very active and non-stationary. The chafing often leads to inflammation and shedding of iris pigment epithelial cells. These cells may then occlude natural aqueous fluid drainage channels. Hindering the drainage channels may cause undesired fluid retention in the eye, thereby increasing intraocular pressure, which is a contributing factor for glaucoma. Such chafing may also lead to other maladies such as, for example, cystoid macular edema and corneal decompensation.
[0003] Present ocular clips not only lead to chafing, they also are very limited in their utility. In other words, the clip is permanently affixed to a lens. Thus, if such a clip fails, the physician must typically replace the entire IOL instead of only replacing the faulty clip.
[0004] Thus, use of traditional ocular clips has declined in favor of advanced suturing techniques. While such suturing techniques are clinically efficacious, they are also complicated and practiced by only highly skilled physicians. The advanced suturing techniques lead to increased procedure time which can result in increased surgical complications, chances for infection, and overall cost and inconvenience to the patient. Late suture breakage, which may occur months or years after the initial suturing is performed, may also lead to a whole new set of complications including IOL dislocation and retinal detachment.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] The accompanying drawings, incorporated in and constituting a part of this specification, illustrate one or more implementations consistent with the principles of the invention and, together with the description of the invention, explain such implementations. The drawings are not necessarily to scale, the emphasis instead being placed upon illustrating the principles of the invention. In the drawings:
[0006] FIG. 1 a includes a front view of a device in one embodiment of the invention.
[0007] FIG. 1 b includes a top view of a device in one embodiment of the invention.
[0008] FIG. 1 c includes a top view of a device in one embodiment of the invention.
[0009] FIGS. 2-14 include front views of various embodiments of the invention.
[0010] FIG. 15 includes a front view of a device in one embodiment of the invention.
[0011] FIG. 16 includes a front view of a device in one embodiment of the invention.
[0012] FIG. 17 includes a front view of an applicator and an implant in one embodiment of the inventions.
DETAILED DESCRIPTION
[0013] The following description refers to the accompanying drawings. Among the various drawings the same reference numbers may be used to identify the same or similar elements. While the following description provides a thorough understanding of the various aspects of the claimed invention by setting forth specific details such as particular structures, architectures, interfaces, and techniques, such details are provided for purposes of explanation and should not be viewed as limiting. Moreover, those of skill in the art will, in light of the present disclosure, appreciate that various aspects of the invention claimed may be practiced in other examples or implementations that depart from these specific details. At certain junctures in the following disclosure, descriptions of well known devices and methods have been omitted to avoid clouding the description of the present invention with unnecessary detail. Furthermore, in the following discussion and in the claims, the terms “including” and “comprising” are used in an open-ended fashion, and thus should be interpreted to mean “including, but not limited to . . . ”. Also, the term “couple” or “couples” is intended to mean either an indirect or direct mechanical, electrical, or other communicative connection. Thus, if a first component couples to a second component, that connection may be through a direct connection, or through an indirect connection via other devices and connections.
[0014] The present invention constitutes a method and apparatus for ocular fixation. As seen in FIG. 1 a , ocular anatomy consists of the cornea 10 , anterior chamber 20 , iris 30 , posterior chamber 40 , and sclera 90 . An IOL 50 with haptics 60 is shown in replacement of a natural lens. In one embodiment, the invention is practiced as follows. An incision is made into the anterior chamber 20 . An ophthalmic clip applicator 80 and ophthalmic clip 70 are inserted through the incision into the eye. The physician abuts an open clip 70 against the anterior iris 30 and then pierces the iris with the clip.
[0015] In one embodiment of the invention depicted in FIG. 2 , a malleable clip 70 may have a basic “U” shape with ends 72 for piercing ocular tissue. The ends 72 may include barbs with recesses 74 for retaining the clip in ocular tissue. Due to general size limitations inherent to ophthalmic surgery, the clip may have small dimensions, including a maximum inner diameter 71 of approximately 0.05 to 0.5 mm—the approximate width of an IOL haptic. Some embodiments of the invention may include a maximum inner diameter 71 of approximately 0.15 to 0.3 mm.
[0016] Returning to FIG. 1 , after piercing the iris, the clip ends 72 are positioned across an IOL haptic 60 . The physician then depresses a lever 81 on the ophthalmic clip applicator 80 , thereby causing cam link 82 to constrict applicator members 1510 , 1520 about the clip 1570 ( FIG. 15 ). Thus, the physician manipulates the ophthalmic clip applicator 1580 to couple the ophthalmic clip 1570 to the haptic 60 and iris 30 . The physician then removes the ophthalmic clip applicator from the eye.
[0017] In one embodiment of the invention, the clip 70 is pierced through the peripheral portion of the iris 30 . By doing so, iris chafing is reduced as compared to affixing the clip 80 to the inner iris because, for example, the peripheral iris is more static and less active than the inner iris. In addition, the invention is not limited to an anterior approach. The clip may be deployed using a posterior approach whereby the haptic 60 is located in either the anterior chamber 20 or posterior chamber 40 . Thus, the haptic may be held between the end portions 76 of the clip and the iris ( FIG. 1 b ). However, the haptic may also be held between the main body of the clip 75 and the iris ( FIG. 1 c ). Regardless, the clip 70 is deployed to hold the haptic 60 against the iris 30 .
[0018] In addition, the clip 70 is not limited to affixing IOLs to the eye. The clip may be used to repair, for example, scleral tears, conjunctival tears, irregularly shaped iris tissue, or iris and corneal tissue injuries. These clips may also be used to secure both lamellar or full-thickness corneal surgery (e.g., corneal transplantation). In one embodiment of the invention, the physician inserts an ophthalmic clip applicator and an ophthalmic clip into the eye. The physician or health care provider then manipulates the ophthalmic clip applicator to couple the ophthalmic clip to a first ocular tissue and a second ocular tissue. The physician then removes the ophthalmic clip applicator from the eye. In a certain embodiment of the invention, the physician couples the ophthalmic clip to a first portion of the sclera that includes the first ocular tissue and a second portion of sclera that includes the second ocular tissue. In another embodiment of the invention, the physician couples the ophthalmic clip to a first portion of the iris that includes the first ocular tissue and a second portion of iris that includes the second ocular tissue. In yet another embodiment of the invention, the physician couples the ophthalmic clip to a first portion of the iris that includes the first ocular tissue and a first portion of sclera that includes the second ocular tissue. In short, the clip may be used to couple various portions of the eye and is therefore beneficial for numerous ophthalmic procedures.
[0019] FIGS. 1 a , 15 , and 16 illustrate various embodiments of a surgical clip applicator. FIG. 16 shows an applicator 1600 that comprises a housing 1680 , and a handle assembly 1650 , 1651 , 1660 coupled to the housing 1680 . The applicator 1600 also includes a jaw assembly including jaws 1610 , 1620 which extend distally from the housing 1680 . The jaw assembly is movable from an open position to a closed position using mechanics 1670 , 1671 , 1640 , 1641 , 1630 , 1631 known to those of ordinary skill in the art. In one embodiment of the invention, a clip 70 ( FIG. 2 ) is coupled to the jaw assembly in an open state. When the jaw assembly is manipulated into a closed position, the clip 70 is closed.
[0020] In one embodiment of the invention, the clip applicator 1580 may employ applicator members with cutting edges (not illustrated). Thus, the physician may first pierce ocular tissue with the cutting edges before deploying a clip that does not possess cutting edges. Applicator members dedicated for cutting ocular tissues may be used in cooperation with other applicator members dedicated to clip deployment (i.e., applicator members that do not employ cutting edges).
[0021] Other embodiments of the applicator may have similar pincher mechanisms and internal mechanics such as those found in, for example, Flexline™ Vitroretinal instruments from Medtronic. As those of ordinary skill in the art will appreciate, such applicators have similar ergonomic designs and mechanics so as to be readily adoptable by physicians. U.S. Pat. No. 5,868,761 discloses a representative applicator. More specifically, a clip applicator may include a handle housing formed from a pair of housing halves and secured together in a conventional manner. The handle housing may enclose a pair of handle members which are pivotable about a pivot point at the proximalmost point of the handle housing. An elongated body portion may extend from the handle housing and terminate in a jaw assembly for crimping clips upon actuation of the handle members. With reference to the handle housing, the handle members include pivot holes which are positioned about a pivot post on the handle housing halves. Pivot post, along with post members, which fit into holes, secures the housing in a snapfit-type arrangement, although other suitable means for securing the handle halves together in a conventional manner is acceptable. The handle housing halves include boss members which facilitate assembly of the components positioned within handle housing, and define a path of travel for several of the components within the handle portion. Located within the handle housing may be a cam link, which serves to advance the channel assembly to close the jaw members towards each other to crimp a clip positioned there between. The cam link may include a pair of angled slots, into which fit pins of handle members, so that as handle members are closed, pins ride within slots to drive the cam link in a distal direction. Releasing the handles permits a compression spring to drive the cam link in a proximal direction, retracting channel assembly from the jaw assembly to open the jaw members to permit the next clip in the series of clips to be fed between the jaw members. The feeding process is accomplished by a feed spring which urges a spring guide in a distal direction to advance a pusher rod, which extends through the cam link, into the elongated body portion. The pusher rod abuts against an indicator, to urge the indicator in the distal direction. The indicator abuts a proximal end of pusher nose, which in turn abuts against the series of clips to urge the clips in a distal direction and into position between the jaw members. Of course in other embodiments of the invention, the applicator may be as simple as conventional forceps that may be manipulated to deploy the implantable device in the eye.
[0022] Turning to FIG. 3 , an additional embodiment of the present invention is illustrated. An ophthalmic clip 70 has first 72 and second ends 73 . The first end forms a cutting surface for piercing ocular tissue. The second end abuts the first end. As seen in FIG. 17 , the clip 1770 may be resilient whereby in a relaxed state, the ends 1771 , 1772 abut one another. The clip 1770 , housed within an applicator 1740 , may be deployed into the eye. The clip 1770 may then be positioned outside the applicator 1740 . Force may be exerted by the applicator extensions 1730 , 1731 in an outward direction, thereby separating clip ends 1771 , 1772 from one another in a stressed state. The clip 1770 may then be positioned to couple, for example only, a haptic to the iris. The applicator extensions 1730 , 1731 may then be relaxed and the clip 1770 returned to its unstressed state. In the alternative, the ends of a clip may abut one another only when compressed. Of course, in alternative embodiments of the invention the two ends are separated by a small space once implanted in the eye. A person of ordinary skill in the art will appreciate that the present invention is not limited to having only one or two ends.
[0023] FIG. 4 discloses a barbless clip. FIG. 5 discloses a barbed clip with barbs facing inward. FIGS. 6 , 7 , 10 , and 11 disclose clips with receptacles 73 for coupling to cutting ends 72 . For example, FIG. 6 may function in a manner similar to a “zip tie” wherein the shaft portion has ledges that allow for graduated advancements of the shaft through the orifice 73 . FIG. 11 may include a body 75 constructed of a suture like material such as, for example, nylon or any other biocompatible, flexible, suture-like material. FIG. 9 discloses an embodiment of the invention whereby each end 72 , 73 of the clip 70 comprises a cutting edge. Once the ends penetrate ocular tissue, the recesses 74 secure the clip and prevent the ends from withdrawal from the tissue. In this embodiment, the ends need not abut, overlap or even finally reside near one another. In another embodiment of the invention, only one end 74 pierces ocular tissue. For example, one end 72 might pierce the iris from the anterior side, and then pierce the optic of an IOL while the other end 73 remains on the anterior side of the iris. In another embodiment of the invention, one end 72 might pierce the iris from the anterior side, and then pierce the optic (i.e., device need not couple to a haptic) of an IOL. In another embodiment, one end 72 might pierce the iris from the anterior side, and then capture the haptic of an IOL. In some embodiments of the invention, the optic or haptic that is to be pierced may have predrilled holes for receiving the haptic. The optic or haptic may instead have a region comprising a more easily penetrable material for promoting piercing by the clip.
[0024] End 73 may be pointed or blunted (e.g., FIG. 8 ). The clips may be resilient and may be deployed into the eye in a compressed state, such as that shown in FIG. 13 . The clip may then resume a noncompressed state once deployed in the eye. That noncompressed state may place the apparatus in a linear form in one embodiment of the invention. FIG. 14 illustrates another embodiment of the invention whereby a guide wire, similar to those used in PTCA procedures, is used. Thus, the physician inserts the piercing end 72 of the device through ocular tissue and/or the haptic. Once penetration has occurred, the guide wire is removed leaving the clip 70 in place. The aforementioned clips may be composed of, for example, at least one of the following materials: titanium, gold, platinum, steel, nylon, polymethyl methacrylate, polyethylene (e.g., high density polyethylene), silicone, hydrophobic or hydrophilic acrylic and polypropylene, or suture-like materials.
[0025] While the present invention has been described with respect to a limited number of embodiments, those skilled in the art will appreciate numerous modifications and variations therefrom. It is intended that the appended claims cover all such modifications and variations as fall within the true spirit and scope of this present invention.
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In an embodiment of the invention, a method includes using an implantable ocular clip to fix an intraocular lens to an iris, all without having to use a suture to permanently hold the lens in place.
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TECHNICAL FIELD
[0001] The invention generally involves devices, such as stents, that are useful for maintaining the patency of a body canal, their delivery systems, and related uses.
BACKGROUND INFORMATION
[0002] The ureter is a fibromuscular tube that conveys urine from the kidney to the bladder. The ureter begins with the renal pelvis and enters the bladder at an area called the trigone. The bladder trigone is the triangulated area between both ureteral orifices and the bladder neck. A normal length for an adult ureter is approximately 16 to 18 inches.
[0003] Ureteral stenosis, stones in the ureter, and other medical conditions call for the use of a ureteral stent or prosthesis. Currently available types of indwelling ureteral stents are variations of the same basic tube structure. The outer and inner diameter, and the size of the drainage holes or the retention elements that are to be placed in the kidney and bladder vary among the known stent types. None of the known ureteral stents adequately address the pain generally associated with an indwelling ureteral stent.
[0004] Ureteral pain associated with a stent is thought to arise from the following: 1) contact between the stent and the mucosal lining of the ureter, or, especially, with the bladder trigone; 2) flank pain from vesico-ureteral reflux which occurs primarily during voiding; and 3) irritation caused by the stent in the intramural tunnel of the urinary bladder wall which is 1-2 cm proximal to the ureteral orifice.
[0005] After an invasive surgical procedure to remove a kidney stone from a patient's ureter, the lining of the ureteral lumen tends to be swollen and inflamed. Post-surgical stent placement, therefore, poses a particular challenge in terms of patient comfort.
[0006] Pain and discomfort associated with indwelling stents or prostheses is not unique to the ureter. Other body canals, for example, blood vessels such as the coronary vessels, and bile ducts, can also benefit from a new stent design that alleviates the pain associated with stents while maintaining the patency of the body canal.
[0007] In addition, an interventional device such as a stent that can better accommodate the anatomy of body canals is needed. Such a device would not only conform to the shape and length of a body canal, the device would also adjust, preferably automatically, to changes in the shape and length of the body canal that occur, for example, during normal bodily functions.
SUMMARY OF THE INVENTION
[0008] It is an objective of the invention to provide a patient, male or female, with a flexible device designed to maintain the patency of a body canal while minimizing the pains and discomfort commonly associated with an indwelling device. Such body canals include and are not limited to the ureter, the urethra, the bile duct, the esophagus, the intestine, the colon, and blood vessels.
[0009] The invention achieves its objectives by minimizing mucosal contact between an interventional device and a targeted body canal and preserving the natural tortuousness of the body canal. For example, by keeping the ureter in its natural tortuous state after implanting an embodiment of the invention, ureteral reflux is effectively prevented during voiding. Specifically, the invention provides an elongated device that include a plurality of discrete loops linked through multiple flexible connections where the loop members can move in multiple directions in relation to another.
[0010] The invention provides an interventional device that has an end-piece at each end and an elongated body portion in between. The body portion has multiple interconnected loops that are sized to fit within the targeted body canal. Each loop is made of a member that defines at least one opening. And each loop is linked to at least another loop through passing its member through at least one opening in another loop. In a particular embodiment, at least one loop member passes through the openings of at least two other loops. In another embodiment, at least one loop member passes through one or two loop openings.
[0011] The loops in the device according to the invention minimize mucosal contact with the body canal. The flexible connections between the loops also allow the elongated body portion to conform to the anatomy of a body canal without compromising the tortuousness of the body canal. Additional flexibility in conforming to the anatomy of a body canal may result from using a radially compressible material for at least part of the body portion. Also because of the flexible connections between the loops, the longitudinal length of the body portion is adjustable, i.e., the body portion is axially compressible. The loops may assume various shapes and structures.
[0012] The body portion may further include a non-loop segment such as a tubular segment. Preferably, the non-loop element has an uneven surface that may help prevent stenosis after the device is implanted in a body canal. The non-loop element may further be made of a radially compressible material.
[0013] The end-pieces may serve as a retention device. In a particular embodiment, an end piece is substantially spherical and prevents migration of the interventional device once properly positioned.
[0014] In another embodiment of the invention, a drug-dispenser is associated with the device of the invention. The drug-dispenser may be a drug-releasing plug or disk, or a coating on at least a portion of the device.
[0015] Another aspect of the invention relates to a delivery assembly that can be used to deliver an interventional device to a target site in the body. According to this aspect of the invention, a stylet is reversibly attached to a proximal end-piece of the interventional device and lends sufficient rigidity to the device that once the stylet is pushed up a body canal, it advances the interventional device along with it. In one embodiment where the stylet is used to deliver the interventional device of the invention, the stylet is free of the body portion and the distal end-piece of the device. In one embodiment, the stylet is reversibly attached to the proximal end-piece of the interventional device through a luer linkage. In another embodiment, the proximal end of the stylet is a malecot which assists in the attachment of the stylet to the proximal end-piece of the device of the invention.
[0016] Embodiments of the invention may include additional features. For instance, a retrieval suture may be attached to the distal end-piece of the interventional device of the invention to assist the removal of the device from the body. The device of the invention may also be made of a biodegradable material, eliminating the need for removal. The device may further include a radiopaque marker. The device may be made of a biocompatible material such as a polymeric material or a metal.
[0017] A method is provided for retaining body canal patency in a patient, which comprises inserting the interventional device of the invention into a body canal and positioning a prxoimal end-piece at one end of the body canal such as the kidney and a distal end-piece at the other end, such as the urinary baldder.
[0018] The foregoing and other objects, aspects, features, and advantages of the invention will become more apparent from the following description including drawings and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention.
[0020] [0020]FIG. 1 is a schematic view of an embodiment of an interventional device according to the invention.
[0021] [0021]FIG. 2 is a schematic view of another embodiment of an interventional device according to the invention.
[0022] [0022]FIGS. 3A and 3B illustrate various embodiments of non-loop segments in the body portion of a device according to the invention.
[0023] FIGS. 4 A- 4 G illustrate various embodiments of the loops according to the invention.
[0024] [0024]FIG. 4H illustrates a cross-sectional view of a loop member of the device of FIG. 4G taken at line “ 4 H- 4 H.”
[0025] [0025]FIG. 4I illustrates the device of FIG. 4G with drug-releasing plugs or discs.
[0026] [0026]FIG. 5A illustrates a cross-sectional view of the body portion of the device of FIG. 1 taken at line “ 5 A- 5 A.”
[0027] [0027]FIG. 5B illustrates a cross-sectional view of the proximal end-piece of the device of FIG. 1 taken at line “ 5 B- 5 B.”
[0028] FIGS. 6 A- 6 D illustrate various embodiments of the end-piece of the interventional device according to the invention.
[0029] [0029]FIG. 7 illustrates an embodiment of the invention positioned in the lumen of the ureter of a patient.
[0030] [0030]FIG. 8 illustrates an embodiment of the device with a delivery assembly.
[0031] [0031]FIG. 9A illustrates an embodiment of a delivery assembly according to the invention.
[0032] [0032]FIG. 9B illustrates another embodiment of a delivery assembly reversibly attachable to the interventional device according to the invention, with the delivery assembly detached from the interventional device.
[0033] [0033]FIG. 9C illustrates the delivery assembly of FIG. 9B with it being attached to the interventional device.
[0034] [0034]FIG. 9D illustrates another alternate embodiment of a delivery assembly reversibly attachable to the interventional device according to the invention, with the delivery assembly detached from the interventional device.
[0035] [0035]FIG. 9E illustrates the delivery assembly of FIG. 9C with it being attached to the interventional device.
DESCRIPTION
[0036] “Distal” is used here to describe an end that is farther away from an origin of attachment. For a device that is at least partly implanted in a patient's body, its distal end is the end closest to an orifice on the patient's body through which the device enters, while its proximal end is the end deepest inside the patient's body.
[0037] The device of the invention is designed to maintain the patency of a body canal while simultaneously minimizing contact with the lining of the canal and preserving the anatomy of the canal. To that end, a common feature of each of the embodiments of the invention described herein is a plurality of interconnected loop-like elements that form a flexible, elongated body portion for insertion into the body canal. These loop elements each resembles a closed or nearly closed figure. Each loop is made of a member curved or doubled over defining at least an opening. And each separate loop member passes through at least one opening of another loop, forming a plurality of interconnected loops out of discrete loop members. Besides the interconnected loops, the elongated body portion of the device of the invention may also include one or more non-loop segments. The interventional device of the invention further includes a proximal end-piece and a distal end-piece, both of which may serve as a retention device.
[0038] For the elongated body portion of the interventional device of the invention, one source of flexibility arises from connections between loops where one loop connects with an adjacent loop at one of a variety of angles, allowing the elongated body portion to be reduced or extended to various pre-determined lengths. The other source of flexibility of the elongated body portion is the radial compressibility of the material used to manufacture individual loops. A delivery system for introducing the interventional device according to the invention is also provided herewith.
[0039] Referring to FIG. 1, device 10 generally includes a proximal end-piece 20 , a distal end-piece 40 , and an elongated body portion 30 . The proximal end-piece 20 and the distal end-piece 40 may serve as retention devices to hold the proximal and distal ends of the device 10 at a specific anatomical location. For example, a specific anatomical location includes but is not limited to the renal pelvis, urinary bladder, or a blood vessel. Each end-piece 20 , 40 is depicted as an embodiment having a substantially spherical shape in FIGS. 1 and 2, however, the shape of the end-pieces 20 , 40 include other embodiments known to the skilled artisan and are not limited to those illustrated.
[0040] Referring still to FIG. 1, in an embodiment according to the invention, the body portion 30 includes a plurality of interconnected loops 33 , which collectively resemble a chain. The length of the elongated body portion 30 is determined by the length of the body canal in which the interventional device 10 is to be inserted. For example, for positioning in the ureter of a patient, the length of the elongated body portion 30 of the interventional device 10 , while varied from patient to patient, is typically about 14-20 inches, preferably about 16-18 inches. Each individual loop 33 includes a loop member 35 that defines at least one opening 31 . The loop member 35 passes through at least one opening 31 of an adjacent loop 33 to make a connection between the two loops. The outside diameter of the loops 33 is determined by the inside diameter of the body canal into which the interventional device 10 is inserted. For example, for the ureter, the outside diameter of the loops 33 may be from about 0.026 inches to about 0.263 inches, and preferably from about 0.039 inches to about 0.197 inches.
[0041] In a particular embodiment according to the invention shown in FIG. 1, a plurality of loops 33 is interconnected in a linear fashion. In this embodiment, each loop member 35 of each loop 33 passes through one or two loop openings 31 . The loop member 35 of a proximal end loop 39 a , illustrated in FIG. 1, passes through the loop opening 31 of one adjacent loop 33 and is joined to a proximal end-piece 20 . The loop member 35 of the distal end loop 39 b passes through the loop opening 31 of an adjacent loop 33 and is joined to a distal end-piece 40 . Each of the loop members 35 between the proximal end loop 39 a and the distal end loop 39 b passes through the openings of two other loops. The proximal end-piece 20 and the distal end-piece 40 are each joined to the adjacent loop member 35 by soldering, welding, adhesive or by other means known to the skilled artisan.
[0042] Referring now to FIG. 2, the elongated body portion 30 may include at least one non-loop segment 32 that is connected to at least one of the loops 33 . The non-loop segment 32 may be any shape, such as a tubular segment or a spiral segment, and is not limited to the shape illustrated in FIG. 2. The non-loop segment 32 may be joined to the rest of the body portion 30 through a variety of connections. In a particular embodiment shown in FIG. 2, each end of the non-loop element 32 is joined to a loop 33 . The loop 33 is in turn interconnected to other loops 33 in the elongated body portion 30 . The non-loop segment 32 may be disposed at either end of the body portion 30 or anywhere between the ends of the body portion 30 .
[0043] The non-loop segment 32 in the elongated body portion 30 of the device of the invention may have a contoured or uneven surface. These surfaces are designed to prevent stenosis and to help maintain a passage for fluid. In one embodiment, referring to FIG. 3A, the body portion of the non-loop segment 32 has an undulated surface. In another embodiment, referring to FIG. 3B, the surface of the non-loop segment 32 includes a longitudinal groove 16 . In yet another embodiment, the element 32 is made of a compressible material that allows some adjustment in its diameter.
[0044] Referring now to FIGS. 4 A- 4 I, the loops 33 and loop members 35 of the elongated body portion 30 can be of any shape that helps maintain the patency of a body canal. For example, the loops 33 can be substantially oval as illustrated, for example, in FIG. 4A, or substantially circular as illustrated, for example, in FIG. 4E, or substantially rectangular, for example, as illustrated in FIG. 4D. Having multiple, discrete but interconnected loops 33 in the body portion 30 is advantageous over known devices because it minimizes mucosal contact between the interventional device 10 and the lining of the body canal in which the device 10 is placed while simultaneously holding the body canal open to allow fluid to pass around the device 10 .
[0045] In another embodiment, the loop member 35 may define more than one opening. For example, referring to FIG. 4C, the loop member 35 may define three openings 31 that are arranged parallel to the longitudinal axis of the body portion 30 . In this embodiment, loop members 35 includes a middle ring 75 flanked by a first side ring 77 a and a second side ring 77 b opposite the first side ring 77 a . In this particular embodiment, each of the side rings 77 a , 77 b passes through an opening 31 of an adjacent loop 33 .
[0046] In one embodiment according to the invention, the loop member 35 may be closed, i.e., loop member 35 has no ends, for example, as shown in FIG. 4A. In an alternate embodiment, referring to FIGS. 4G and 4H, the loop member 35 may be open with two unconnected ends 14 a and 14 b . A gap 12 is located between the two ends 14 a and 14 b . The width of the gap 12 indicated in FIG. 4G is less than the diameter 45 of the adjacent loop member 35 indicated in FIG. 4H, so that the adjacent loop member 35 will not dislodge from the loop 33 .
[0047] The loop member 35 in accordance with the invention may be made by, for example, bending a cylindrical length of material into a closed or nearly closed figure. In one embodiment, the cylindrical material itself may be twisted about its longitudinal axis, for example, as shown in FIG. 4E. The cylindrical piece may be solid, which will give it a substantially circular cross section as shown in, for example, FIG. 2. Or the cylindrical piece 35 may be hollow, including one or more lumens 34 , as illustrated in cross section in FIG. 4H. Materials used to manufacture the loop members 35 include, but are not limited to, nickel-titanium, polyurethane (e.g., Tecoflex® material), Flexima™ material, Perculflex® material, C-Flex® material, and silicone, for example.
[0048] According to the invention, each loop 33 moves in the opening 31 of an adjacent loop 33 constrained only by the cross-sectional diameter of each loop member 35 and the diameter of the loop openings 31 .
[0049] Referring again to FIG. 4A, two adjacent loops 33 are shown in more detail. In this embodiment, one loop 33 moves in a direction along the X, Y, or Z axis or a combination of any of the three axes within the confines of the opening 31 of an adjacent loop 33 . That is, the loop 33 forms a flexible connection with the adjacent loop 33 and can move in a plurality of axes. By having multiple flexible connections from loop to loop along the length of the body portion 30 , the body portion 30 can conform to the contour of a body canal. The larger the number of flexible connections per unit length of the elongated body portion 30 , the greater the flexibility of the elongated body portion 30 . Thus, for a more tortuous body canal, a larger number of flexible connections is desirable. Also, by having numerous flexible connections in the body portion 30 , the body portion of the device 10 is automatically adjustable to changes in the shape of the body canal during normal bodily activities, such as during urination.
[0050] An advantage of using a chain-like configuration for the body portion 30 is the volume of space that is generated between loops 33 for the passage of fluid. Referring still to FIG. 4A, a left loop 33 a is shown to lie in an X-Z plane while a right loop 33 b lies in an X-Y plane. The two farthest points in the Y direction on the right loop 33 b are points 71 and 72 while the entire left loop 33 a lies in a plane orthogonal to the Y-axis. The two adjacent loops 33 a and 33 b do not have to be orthogonal to each other. As long as the loops 33 a , 33 b are not in the same plane, space is available between the loops 33 a , 33 b for fluid passage. This feature according to the invention is an important advantage over conventional tubular stents because tissue ingrowth and stenosis may occur after operation is performed on the lining of the body canal. The chain-like body portion of the device 10 according to the invention, minimizes the chance that fluid passage will be completely blocked by tissue ingrowth and sterosis.
[0051] Referring again to FIGS. 4A and 4B, according to one embodiment of the invention, the loop 33 b , moves within the opening of an adjacent loop 33 a , when the loop 33 b , shown in FIG. 4A, experiences a force in the direction denoted by arrow “m.” The combined axial length 80 of the two loops 33 a , 33 b may be reduced by as much as a distance 37 shown in FIG. 4B. Therefore, when multiple loops 33 are linked together, the combined axial length 80 of the body portion 30 becomes adjustable. Because the combined axial length 80 of the body portion 30 is adjustable, it is easier for the interventional device 10 to fit into a body canal of a particular length. Moreover, the adjustability in the combined axial length 80 of the elongated body portion 30 allows the interventional device 10 to automatically adjust to changes in the length of the body canal that occur spontaneously, for example, when a patient moves from a sitting to a standing position. This feature of the internventional device 10 provides greater comfort to the patient.
[0052] Referring again to FIG. 1, in one embodiment of the invention, the end-pieces 20 and 40 of the interventional device 10 of the invention may serve as a retention device at their respective end. In one embodiment according to the invention, the cross-section of end-pieces 20 , 40 have larger area than the cross-section of body portion 30 . For example, a cross-section of the body portion 30 taken at the line “ 5 A- 5 A” in FIG. 1 is shown in FIG. 5A, and a cross section of the proximal piece 20 taken at line “ 5 B- 5 B” in FIG. 1 is shown in FIG. 5B. The cross-sectional diameter 21 of the proximal piece 20 is greater than the cross-sectional diameter 36 of the body portion 30 .
[0053] FIGS. 6 A- 6 D illustrate embodiments of the end-pieces 20 , 40 . Referring now to FIG. 6A, in one embodiment, either the proximal end-piece 20 or the distal end-piece 40 , is substantially spherical. In one embodiment illustrated in FIG. 6B, the end-piece 20 or end-piece 40 , has three arms 43 that extend outward from the center of the elongated body portion 30 to stop migration of the device 10 in the direction indicated by the arrow “k.” In another embodiment, the end-piece 20 or the end-piece 40 , is a coil as shown in FIG. 6C. In the embodiment shown in FIG. 6D, the end-piece 20 or the end-piece 40 may be an inflatable balloon connected to a source of fluid through an infusion channel 25 . The inflatable balloon can be inflated or deflated through the infusion channel 25 .
[0054] Either end-piece 20 or end-piece 40 may be positioned at an anatomical location such as the renal pelvis 51 or the ureteral orifice 61 , illustrated in FIG. 7. Because the diameter of the end-piece 20 , 40 is designed to be larger than that of the body canal, the end-piece 20 , 40 will prevent device 10 from migrating in the direction “k” shown in FIGS. 6 A- 6 D.
[0055] The device 10 according to the invention is made of a bio-compatible material. In one embodiment, according to the invention, all or portions of the device 10 may be made, for example, of a compressible material, such as a metal alloy (e.g., nickel-titanium) or a polymeric material (e.g., polyurethane). Additional suitable materials for the device 10 include Flexima™ material, Perculflex® material, C-Flex® material, and silicone.
[0056] Referring again to FIGS. 4D and 4F, in a particular embodiment, the member 35 of loops 33 of the body portion 30 of the device 10 may be made of a compressible material that, when squeezed, deforms at least in one direction indicated by arrow “f.” The material composition of the loop member 35 lends flexibility so that the device 10 is more likely to conform to the anatomy of the patient's body canal and lessens patient discomfort. Of course, it is not necessary that such compressible material be used, other materials, such as non-compressible metal, can also be used. In a particular embodiment, the device of the invention is made of a biodegradable material, and would not require removal from the patient.
[0057] Referring again to FIG. 1, in a particular embodiment according to the invention, the interventional device 10 may contain one or more conventional radiopaque markers 2 to aid in more precise positioning of the device 10 in a patient's body canal. In a particular embodiment, the markers 2 are placed near the proximal end-piece 20 and the distal end-piece 40 to indicate their positions. The radiopaque markers 2 can be, for example, a metal ring or barium sulfide embedded in the device 10 , or the marker 2 may be a band of radiopaque ink painted on portions of the device 10 . Alternatively, the entire device 10 or the entire body portion 30 may be made of a radiopaque material.
[0058] Referring again to FIG. 4I, the interventional device 10 according to the invention may further contain a drug-dispenser 17 for releasing a drug into the body. Drugs that may be dispensed by the drug dispenser 17 may include anti-microbial or anti-inflammatory reagents to prevent infection and/or inflammation of the body canal where the interventional device 10 is placed. Referring to FIG. 4I, for example, the drug-dispenser 17 may be a drug-containing plug or disk disposed within the body portion 30 of the interventional device 10 . In this case, the drug-dispenser 17 is disposed within loop members 35 of the body portion 30 of the interventional device 10 . In a hollow loop member 35 , illustrated in FIG. 4H, for example, the drug-containing substance may be disposed inside the lumen 34 and dispensed through a lumen aperture 6 on the member 35 , such as the aperture 6 illustrated in FIG. 4G.
[0059] Referring again to FIG. 4C, in another embodiment according to the invention, a drug-releasing coating 18 is deposited on portions of the device, for example, on side rings 77 a and 77 b of the loops 33 . In a particular embodiment, the coating 18 releases the drug in a time-controlled fashion. The coating 18 may include a porous layer containing antibiotics such as ciprofloxacin and a rate-limiting overlayer that results in a constant, sustained release (C. Kwok et al, Journal of Controlled Release 62 (1999) 301-311). Such coating may include an antibiotic-containing hydrogel (J. Pugach et al, Journal of Urology (1999), v. 162, 883-887). Other examples of such coating may be found in U.S. Patent Ser. Nos. 5,902,283 and 5,520,664, the entire disclosure of both incorporated by reference herein.
[0060] [0060]FIG. 7 illustrates a method for using the device of the invention in a patient to treat a patient's body canal 55 , for example, the ureter. A ureter 55 normally directs urine from a kidney 50 into the urinary bladder 60 . The ureter 55 extends from the kidney 50 at renal pelvis 51 to the urinary bladder 60 at ureteral orifice 61 . The bladder neck 65 funnels urine into the urethra. The triangulated area between the two ureteral orifices 61 and the bladder neck 65 is the trigone area 63 . Once the device of the invention 10 is positioned within the ureter 55 , as described below, the device 10 maintains patency of the ureter 55 for passage of urine between the renal pelvis 51 and the urinary bladder 60 .
[0061] In an embodiment of the invention for placing and using the device 10 in the body canal, such as the ureter of the patient, the operator uses a trans-urethal approach and uses a guidewire and a cystoscope to aid in placement of the interventional device 10 in the ureter. As illustrated in FIG. 7, the proximal end-piece 20 is positioned in the renal pelvis 51 and the distal end-piece 40 is positioned in the lumen of the urinary bladder 60 . The elongated body portion 30 extends from the distal end-piece 40 in the urinary bladder 60 , through the intramural canal of the urinary bladder wall and the lumen of the ureter 55 to the proximal end-piece 20 in the renal pelvis 51 . Following positioning of the interventional device 10 in the ureter 55 , the operator withdraws the guidewire. The interventional device 10 of the invention may be also placed in a body canal via other means such as a transcutaneous means, known to one skilled in the art.
[0062] Still referring to FIG. 7, the interconnected loops 33 of the body portion 30 maintain patency of the ureter 55 for urine passage. In addition, the body portion 30 contacts the lining of the ureter 55 only focally compared to more conventional tubular prostheses that have full contact with the ureteral lining. Further, the flexible connection between loops 33 in the elongated body portion 30 permits the interventional device 10 to readily conform to the anatomy of the ureter 55 , even during ureteral movements. With the tortuous path of the ureter 55 kept largely intact in the presence of the elongated body portion 30 , vesico-ureteral reflux, which occurs primarily during voiding, can be prevented because it is more difficult for fluid to reflex up the ureter 55 when the tortuous path of the ureter 55 is maintained.
[0063] Still referring to FIG. 7, the device 10 may be retained at the renal pelvis 51 by the proximal end-piece 20 . It may be additionally retained at the ureteral orifice 61 , by the distal end-piece 40 . Having an end-piece on both ends prevents the device 10 from migrating, minimizing mucosal irritation and pain stemming from the sliding of body portion 30 within the ureter 55 and minimizing contact between the device 10 and the sensitive trigone area 63 of the urinary bladder 60 . Moreover, the flexible connection between the loops 33 also allows automatic adjustment in the length of the body portion 30 , which helps to adapt the interventional device 10 to ureters 55 of different lengths or to changes in the length of the ureter during bodily functions.
[0064] In another embodiment according to the invention, referring to FIG. 8, a delivery assembly 22 , for example, a stylet 88 , is associated with the proximal end-piece 20 . A retrieval suture 42 , may also be associated with the distal end-piece 40 , which may aid in the removal of the device 10 from the body canal. The retrieval suture 42 may be a thread, a ribbon, a wire, a tape, a suture, or the like. The retrieval suture 42 is attached by its proximal end 42 a by means known to the skilled artisan, and the distal end 42 b is free. The distal free end 42 b may be grasped by the operator to withdraw the interventional device 10 from the body canal.
[0065] Still referring to FIG. 8, in a particular embodiment of the delivery asembly 22 , a stiff stylet 88 is reversibly attachable to the proximal end-piece 20 at an opening 28 in the proximal end-piece 20 . The stylet 88 has sufficient column strength so that, once attached to the proximal end-piece 20 , the stylet 88 can be pushed up a body canal 55 , advancing the rest of the interventional device 10 along with it. The material used to manufacture the stylet 88 is flexible so that the flexibility of the interventional device 10 being delivered is not substantially compromised. Suitable materials for the stylet 88 include but are not limited to C-Flex® materials, or Flexima™ material. In a particular embodiment, the stylet 88 is associated with the device 10 only at the proximal end-piece 20 , and is free of the body portion 30 and the distal end-piece 40 .
[0066] Referring now to FIG. 9A, in an embodiment according to the invention, the proximal end 23 of the stylet 88 fits into an opening 28 in the proximal end-piece 20 , allowing an operator to use the stylet 88 to push the device 10 up the body canal 55 . Once the device 10 is placed properly in the body canal 55 , the proximal end 23 of the stylet 88 can be pulled out of the opening 28 in the reverse direction as the style 88 is withdrawn from the body canal 55 .
[0067] Referring to FIGS. 9 B- 9 C, in another embodiment according to the invention, the proximal end 23 of the stylet 88 is a male luer portion having spiral threads that fit into a complementary female luer portion of the opening 28 of the proximal end-piece 20 . The male luer portion 23 is seated in the female luer portion 28 by twisting the stylet 88 in one direction. Once the interventional device 10 is placed properly in the body canal 55 , turning the stylet 88 in the reverse direction will detach the style 88 from the proximal end-piece 20 .
[0068] In another alternate embodiment according to the invention, illustrated in FIGS. 9D and 9E, the proximal end 23 of the stylet 88 comprises a malecot. A spring-tensioned wire 27 is connected to a proximal tip 29 of the stylet 88 . Actuating the wire 27 by pulling the wire 27 in the distal direction will cause the arms 24 of the malecot to extend laterally, seating the proximal end 23 of the stylet 88 in the opening 28 and preventing the proximal end 23 from slipping out. Releasing the wire 27 collapses the arms 24 of the malecot 23 and enables the operator to detach the stylet 88 from the proximal end-piece 20 and to withdraw the stylet 88 from the device 10 .
[0069] Variations, modifications, and other implementations of what is described herein will occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the invention is to be defined not by the preceding illustrative description but instead by the spirit and scope of the following claims.
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A device is provided for insertion and implantation in a patient's bodily canals or vessels such as the ureter. The device includes interconnected loops that form a flexible structure that may span the length of a bodily canal. The device may include retaining elements at both or either ends. Further according to the present invention, there is provided a stylet for delivering the device to the desired body canal. The device minimizes contact with the lining of the bodily canal while retaining the patency of the canal. The device also is adjustable in length and shape. It is particularly useful for maintaining the tortousness of a body canal.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to subassemblies for automobile vehicles including a cooling cassette and a support frame for the cassette.
[0003] 2. Description of the Prior Art
[0004] Subassemblies for automobile vehicles including a cooling cassette supporting a motorized fan unit and a frame supporting the cassette are known in the art. The subassembly constitutes what is sometimes referred to as the technical front bulkhead of the vehicle. At present, the cassette is generally fixed to the frame by means of positive fasteners such as screws. This has drawbacks, however. If the vehicle suffers a frontal impact (such as a standard DANNER impact), causing pressure to be applied to the cooling cassette, the subassembly often fractures, damaging the cassette and the frame.
[0005] One object of the invention is to provide a subassembly of the above kind which improves the chances of the cassette and/or the frame remaining undamaged if the vehicle suffers a frontal impact.
SUMMARY OF THE INVENTION
[0006] To achieve the above object, the invention provides a vehicle subassembly including a cooling cassette provided with at least one cassette element and a frame provided with at least one frame element adapted to cooperate with the cassette element to fix the cassette to the frame, which elements are adapted so that a thrust force applied to a face of the cassette that faces toward the front when mounted in the vehicle causes the cassette element to separate from the frame element.
[0007] Accordingly, in many circumstances, if the impact applies a force toward the rear on the cassette, it separates the cassette from the frame without damaging either of them. It is therefore possible either to refit the cassette to the frame or to replace only the cassette or only the frame with an identical component.
[0008] The subassembly according to the invention can further have at least one of the following features:
[0009] it includes an elastomer stud adapted to be interposed between the cassette element and the frame element;
[0010] the cassette element is adapted to come into contact with the frame element to fix the cassette to the frame;
[0011] one of the two elements of the pair consisting of the cassette element and the frame element is conformed as a male part and the other element of that pair is conformed as a female part adapted to receive the male part;
[0012] the cassette element is conformed as a male part;
[0013] one of the two elements of the pair consisting of the cassette element and the frame element is conformed as a lug and the other element of that pair is conformed to retain the lug with a clipping action;
[0014] the cassette element is conformed as a lug;
[0015] it includes a rib projecting from the face of the cassette that faces toward the front when mounted in the vehicle;
[0016] it includes a motorized fan unit fixed to the cassette, the cassette having a raised portion projecting from the face of the cassette that faces toward the front when mounted in the vehicle and projecting farther toward the front than the motorized fan unit.
[0017] The invention also provides a vehicle including a cooling cassette provided with at least one cassette element and a frame provided with at least one frame element cooperating with the cassette element to fix the cassette to the frame, which elements are adapted so that a thrust force applied to a face of the cassette that faces toward the front when mounted in the vehicle causes the cassette element to separate from the frame element.
[0018] Other features and advantages of the invention will become more apparent in the course of the following description of a preferred embodiment, which description is given by way of non-limiting example and with reference to the accompanying drawing.
BRIEF DESCRIPTION OF THE DRAWING
[0019] [0019]FIG. 1 is an exploded perspective view of a preferred embodiment of a subassembly in accordance with the invention without the motorized fan unit.
[0020] [0020]FIG. 2 is a view in cross section of the frame and the cassette of the subassembly shown in FIG. 1, at the location of a pair of fasteners.
[0021] [0021]FIG. 3 is a view in horizontal section of the subassembly shown in FIG. 1 taken along the line III-III.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0022] FIGS. 1 to 3 show a preferred embodiment of a subassembly in accordance with the invention.
[0023] The subassembly 2 comprises a cooling cassette 4 , a support frame 6 and a motorized fan unit 8 .
[0024] The cassette 4 is thin and generally rectangular. It has in the vicinity of its center a circular opening 10 adapted to receive the motorized fan unit 8 . The cassette 4 also has various raised and recessed portions adapted to receive items that are known in the art and that are not described in detail here. The cassette 4 is vertical when fixed to the vehicle. In this position, the longitudinal sides 12 of the rectangle are horizontal and transverse to the direction of movement of the vehicle. The short sides 14 of the rectangle are vertical.
[0025] The cassette has lugs 20 , of which there are eight in this example, for fixing it to the frame 6 . Each of the four edges 12 , 14 of the cassette carries two of the eight lugs. The lugs extend from the edge of the cassette toward the front, projecting from the face 22 of the cassette that faces toward the front when fixed to the vehicle. Each lug has a generally flat shape and is essentially parallel to the edge that carries it. It also has a boss 24 on one side of the lug, near its free end, for retaining the lug in a fixing orifice described below.
[0026] The frame 6 includes a generally rectangular housing 26 which receives the cassette 4 . The frame also has two horizontal longitudinal sides and two vertical short sides. The top left-hand and right-hand corners of the frame are extended laterally by two extension 28 . The ends of the extensions 28 are adapted to be fixed to the inner wings of the vehicle. Also, the frame 26 has half way up its vertical sides locations 30 for fixing the frame to two longitudinal members of the vehicle.
[0027] The frame includes the same number of tabs 32 as there are lugs 20 , extending from the four sides of the frame into the opening intended to receive the cassette. Each tab 32 is vertical and has a generally flat shape with a rectangular contour. It has an orifice 34 at its center. In this example, the orifice is occupied by an elastomer material stud or shoe 38 having an opening at its center and an annular groove at its periphery adapted to envelop the edges of the opening 34 in the tab to receive and locate the shoe in the opening. The opening 34 in each tab 32 and the central opening in the corresponding shoe are elongate. The opening is adapted to receive one of the lugs 20 . The lugs 20 therefore constitute male parts and the tabs 32 constitute respective female parts which receive them from behind. Consequently, the cassette 4 is mounted on the frame 6 by inserting it into the opening 26 of the frame from behind.
[0028] When the cassette is correctly positioned in the opening, the eight lugs 20 are engaged in the openings 8 in the shoes and are received in the respective tabs. When the lugs are inserted into the shoes 38 , the boss 24 of each lug defines a sticking point that has to be overcome before the lug is properly received in the tab. This sticking point limits the risk of unintentional withdrawal of the lug from the tab on rearward movement of the cassette out of the frame. The lugs are retained firmly in the tabs by the compression force applied to the lugs by the elastomer material shoes. Also, the bosses 24 on the lugs have an additional retaining effect. The cassette is therefore properly fixed into the frame that supports it.
[0029] The cassette 4 carries the motorized fan unit 8 , which is received in its opening 10 , as shown in FIG. 3. The cassette has a raised portion 40 , which takes the form of a vertical rib in this example, projecting from the face 22 of the cassette that faces toward the front when fitted to the vehicle. The rib extends farther toward the front than the motorized fan unit 8 . Accordingly, if the vehicle suffers a frontal impact, for example at a low speed, generating temporary or permanent deformation of the bumper beam 42 , in many circumstances the bumper beam 42 will strike the rib 40 on the cassette before reaching the motorized fan unit. This impact causes the cassette to move toward the rear relative to the frame, extracting the lugs from the tabs. The impact therefore causes localized or total demounting of the cassette from the frame. In many cases neither the cassette nor the frame will be damaged. In particular, the fastenings formed by the lugs and the tabs are protected from any damage. It is therefore possible either to refit the cassette directly to the frame or to replace either the cassette or the frame with a new component. This reduces the cost of repair.
[0030] Moreover, the subassembly in accordance with the invention facilitates standardizing the fixing of the cooling cassettes to the frames.
[0031] The function of the shoes 38 is essentially to damp vibration. In a different embodiment, these shoes could be dispensed with and the lugs clipped directly into the tabs by virtue of the bosses 24 and the ends of the lugs coming into elastic bearing engagement against an edge of the orifice in each tab.
[0032] The invention is particularly suitable for the circumstances of the kind of impact usually referred to as DANNER impact.
[0033] Of course, many modifications can be made to the invention without departing from the scope of the invention.
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A vehicle subassembly includes a cooling cassette provided with at least one cassette element and a frame provided with at least one frame element which cooperates with the cassette element to fix the cassette to the frame. A thrust force applied to a face of the cassette that faces toward the front when mounted in the vehicle causes the cassette element to separate from the frame element.
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